Junior Faculty Programs

• Possess a doctoral-level degree (e.g., MD, PhD, DDS, PharmD)
• Have a full-time junior faculty appointment at one of the four UCLA CTSI partnered institutions (UCLA, Cedars-Sinai, Charles R. Drew University, and Lundquist Institute at Harbor-UCLA) in any series at or above the clinical instructor level as of July 1, 2024.
• U.S. citizen, non-citizen national or permanent resident by July 1, 2024. Individuals on temporary or student visas are not eligible.
• Commit 75% of professional effort to translational research. Those in surgical specialties may request a lower level of effort, but in no case lower than 50%, with the level of CTSI KL2 salary support being reduced proportionately. To request a lower level of effort, please contact CTSIWD@mednet.ucla.edu by the full application deadline so a formal request can be submitted to the NIH.
• Not be or have been a principal investigator on an NIH R01, or project leader on a subproject of a Program Project (P01), Center (P50, P60, U54), mentored career development grant (K23, K08, K01, etc.), or equivalent non-PHS peer reviewed research grant that is over $100,000 in direct costs per year. May have had support on a non-federal grant, a NRSA grant (F or T) or have been PI of an NIH small grant (R03 or R21). Note: Candidates may have had previous support on a K12 award, but the CTSI KL2 cannot extend total K support beyond five years.
• Simultaneous KL2 and NIH K (e.g. K01, K08, K23, etc.) applications.Everyone is encouraged to submit a KL2 pre-application. However, if you submit an NIH K application in January, February or March 2024, you are not eligible to submit a KL2 full application

Project title: Lipid Signaling Network in the Regulation of Hepatocellular Carcinogenesis through YAP/TAZ Activity

Mentors:

Enrique J Rozengurt, PhD - UCLA/VA Greater Los Angeles Healthcare System
Joseph R Pisegna, MD - UCLA/VA Greater Los Angeles Healthcare System
Thomas Vallim, PhD - UCLA Health Sciences
Vatche Agopian, MD - UCLA

Multidisciplinary expertise:
Cancer biology, lipid metabolism, signal transduction, transcriptomics, chemoprevention

Project Description:
Nonalcoholic fatty liver disease (NAFLD) has reached pandemic proportions. One of its most consequential complications, hepatocellular carcinoma (HCC), is also on the rise and predicted to become the leading indication for liver transplantation. As liver transplantation remains a scarce resource, especially in NAFLD-related HCCs where patients tend to present sicker, early detection and chemoprevention are imperative. Statins have been associated in large, retrospective, observational studies to decrease the incidence of HCC, however their mechanism(s) of action remains elusive. In this proposal, we aim to study the interplay between lipids, statins, Rho GTPases and the YAP/TAZ oncogenic pathway in hepatocarcinogenesis, which has recently been implicated in HCC. Our findings have the potential to identify novel chemo-preventative methods, especially in light of ongoing randomized controlled trials assessing statin benefits in patients with cirrhosis to prevent cirrhosis complications and HCC development.

Project title: Impact of Genetically Regulated Neuro-Immune Gene Expression on Childhood Brain Development

Mentors:

Daniel Geschwind, MD, PhD – UCLA
Susan Bookheimer PhD – UCLA
Michael Gandal – University of Pennsylvania
Wesley Thompson – Laureate Institute for Brain Research

Multidisciplinary Expertise:
Neuroscience, statistical genetics, functional genomics, neuroimaging

Project Description:
Altered neuro-immune gene expression has been observed in postmortem brain tissue from individuals with neurodevelopmental, psychiatric disorders. Neuro-immune pathways also play a critical role in typical neurodevelopment, including age-related pruning of synaptic processes. One mechanism by which neuro-immune function may affect the brain is through effects on synaptic pruning during development; however, the effects of neuro-immune gene expression on in vivo brain development are not known. Through a coordinated set of multimodal analyses integrating genetics, transcriptomics, and in vivo neuroimaging, this project aims to define the genetic architecture of brain gene expression and to test the relationship between individual’s predicted brain gene expression and in vivo neuroimaging measures in a largely typically-developing, population-based cohort of children. This research will expand our understanding of the genetic mechanisms regulating gene expression in the human brain and may ultimately aid in the prospective identification of youth at increased genetic risk for mental illness.

Project title: Examining the Effect of Collaborative Learning on Adolescent Social Networks and Substance Use

Mentors:

Mitchell Wong, MD, PhD – UCLA
Ronald Hays, PhD – UCLA & RAND Corporation
Ziva Cooper, PhD – UCLA
Joan Tucker, PhD – RAND Corporation
Rebecca Dudovitz, MD – UCLA

Multidisciplinary Expertise:
General Internal Medicine and Pediatrics, Social Network Analysis, Substance Use Prevention, School-based Interventions, Social Determinants of Health

Project Description:
This project examines how collaborative learning – a group-based pedagogical technique promoting interdependence and prosocial interactions between students – may promote salubrious social networks and prevent adolescent substance use. From ongoing qualitative interviews, we will develop a novel multidimensional measure of collaborative learning.  We will then survey 600 9th-12th grade students, half enrolled in a collaborative learning intervention and half enrolled in traditional high school. From this survey, we will test whether the intervention is associated with a reduction in substance use and misuse and healthier social networks. Finally, we will use the novel measure of collaborative learning to identify which construct dimensions are most closely associated with substance use and risky behaviors.

Project title: Elucidating the Role of Biofilm-Forming Bacteria in Nephrolithiasis

Mentors:

Gerard Wong, PhD - UCLA
George O’Toole, PhD - Dartmouth
Margaret Pearle, MD, PhD - UT Southwestern
Paul Boutros, PhD, MBA - UCLA

Multidisciplinary expertise:
Renal and ureteral physiology, molecular biology

Project Description:
Kidney stone disease is an increasingly prevalent disease. However, its pathogenesis is still poorly understood. Recent publications have utilized next-generation sequencing to identify bacterial infestation in calcium stones despite no evidence of prior or concurrent urinary tract infection in those patients. We hypothesize that bacteria interact with calcium stones and that this interaction plays a key role in the propagation of kidney stones. We will test this hypothesis using three specific aims: 1) to investigate stone biofilm formation and 2) to investigate a role for surface sensing in the bacteria-kidney stone interaction and 3) to investigate how bacteria respond to urine-specific environments and kidney stone propagation using an in vitro three-dimensional kidney model. These aims will be accomplished by utilizing multiple imaging and complementary quantitative techniques, as well as single-cell analyses and molecular genetic techniques to investigate biofilm initiation.

Project title: Identification of Novel Virulence Factors on Multi-Drug Resistant Candida Auris for Vaccine Development Strategies

Mentors:

Ashraf Ibrahim, PhD – Lundquist Institute, Harbor-UCLA Medical Center
Scott Filler, MD – Lundquist Institute, Harbor-UCLA Medical Center
John E. Edwards Jr., MD – Lundquist Institute, Harbor-UCLA Medical Center
Bruce Klein, MD – University of Wisconsin-Madison 

Multidisciplinary Expertise:
Infection and immunity, Molecular pathogenesis, Antigen discovery, Vaccine and immunotherapy development, In vivo infection models

Project Description:
Discovered only about a decade ago, Candida auris has quickly emerged as a global health concern. C. auris can withstand extreme environmental conditions, persist on human skin, and thrive on inanimate objects found in healthcare-settings, thereby frequently causing healthcare-associated infections in immunocompromised, hospitalized patients. Patients harboring indwelling medical devices such as central venous catheters, cardiac stents, shunts, or urinary catheters are at a higher risk of infection since C. auris can form multidrug-resistant (MDR) biofilms on these devices. Due to these reasons, the Centers for Diseases Control and Prevention has identified C. auris as one of the “Urgent Threat” pathogens in its 2019 Antibiotic Resistance Threats Report. Therefore, to combat C. auris infections alternative therapeutic strategies are urgently needed. Ironically, hardly anything is known about the virulence traits of C. auris and their potential as therapeutic targets. We will use cutting edge proteomics and bioinformatics approach to identify novel C. auris surface proteins and study their role in virulence. Finally, we will develop selected antigens as vaccine candidates against C. auris infection using advanced mRNA-based vaccine technologies.ar of recovery. 

Project title: Imaging transcriptomics across developmental stages of early psychotic illness

Mentors:

Carrie Bearden, PhD – UCLA
Michael Gandal, MD, PhD – UCLA
Bogdan Pasaniuc, PhD – UCLA
Armin Raznahan, MD, PhD – NIMH
Nelson Freimer, MD – UCLA

Multidisciplinary Expertise:
Schizophrenia/Psychosis, Neuroimaging, Neurobehavioral genetics, Neurodevelopment

Project Description:
Schizophrenia is a neurodevelopmental disorder often resulting in profound chronic disability with overt clinical onset most common during adolescence. The progression to psychosis is dynamic and protracted, and working memory dysfunction is a core feature of schizophrenia with typical maturation throughout adolescence, which depends partly on cortical glutamate- and GABA-mediated neural circuitry. However, connecting the molecular underpinnings of disruptions in this circuitry to in vivo human brain development has been elusive. This integrative project utilizes novel neuroimaging methods and publicly available brain wide transcriptomic atlases to investigate neurodevelopmental mechanisms of schizophrenia risk in a prospective longitudinal cohort of youth at clinical high-risk (CHR) for psychosis. The project will test whether cortical regions underlying working memory function are differentially affected in CHR youth that develop schizophrenia, and whether they are associated with working memory measures and a unique pattern of glutamate and GABA transcript enrichment affected by schizophrenia risk genes.

Project title: Neuro-immune regulation of asthmatic airway hyperresponsiveness and inflammation

Mentors:

Richard Casaburi PhD MD, Lundquist Institute, Harbor-UCLA Medical Center
Harry Rossiter PhD, Lundquist Institute, Harbor-UCLA Medical Center
Virender Rehan MD, Lundquist Institute, Harbor-UCLA Medical Center
Jack Feldman PhD, UCLA
Mannish Butte MD PhD, UCLA

Multidisciplinary Expertise:
Neuroscience, immunology, neuroimmunology, physiology, bioinformatics

Project Description:
Despite mainstay immunosuppressive therapies, asthma remains one of the costliest chronic diseases, affecting millions of Americans. The allergic response triggers many asthmatic symptoms of neurogenic origin, and emerging evidence highlights the crucial role of neural regulation of immunity. However, the communication between tissues and nerves, and reflex integration is poorly understood warranting further investigation. This project explores the hypothesis that complementary neuroendocrine-neuron clusters become sensitized with allergic asthma and exacerbate asthmatic inflammation and reflex mediated bronchoconstriction. We will investigate the cellular mechanisms involved in neuroendocrine-neuron hypersensitization and conduct studies to test how suppression of these mechanisms may quell asthmatic inflammation in vivo. These studies will increase our understanding of neuroimmune regulation in allergic asthma and provide the potential to target novel pathways for pharmaceutical development.

Project title: Examining the modulatory role of the sleep-wake cycle and adenosine in migraine - a focus on cortical spreading depression and sensory sensitivity

Mentors:

Andrew Charles, MD, PhD - UCLA
Guido Faas, PhD – UCLA

Multidisciplinary Expertise:
Migraine pathophysiology, Sleep physiology, Astrocyte signaling

Project Description:
Migraine is a chronic and disabling condition characterized by recurrent and severe headache pain. Migraine is common, affecting 1 out of every 5 Americans, and carries a significant economic and health burden in the United States and worldwide. Clinically, migraine and sleep disturbances are often co-morbid. While migraine attacks can be triggered by sleep deprivation, migraine headache is commonly relieved by sleep. Despite both clinical and pre-clinical evidence illustrating a role for sleep in migraine pathophysiology, there remains a lack of understanding of the molecular and cellular players that exert sleep-induced changes on migraine susceptibility. Utilizing novel micro-electronic technologies, this project works to clarify the complex relationship between the sleep-wake cycle and two key aspects of migraine pathophysiology – cortical spreading depression and sensory sensitivity. By examining the role of adenosine, a drug-modifiable target, in modulating sleep-related changes in migraine pathophysiology, this project aims to identify novel therapeutic targets for migraine.

Project title:  Bio-inspired Electrospun Urethral Scaffold Design: Biomechanical, Structural and In vitro Evaluation

Mentors:

Nasim Annabi – UCLA
Song Li – UCLA
Isla Garraway – UCLA
Ali Khademhosseini – Terasaki Institute

Multidisciplinary Expertise:
Bioengineering, chemical engineering, scaffold design, biomechanics, cell-material interactions, reconstructive surgery

Project Description:
Urethral defects requiring urethroplasty (repair of urethral tube) occur in children and adults secondary to congenital, traumatic, infectious and malignant conditions. Current tissue sources for urethral replacement are limited by donor site morbidity and lack of optimal tissue characteristics to support lifelong voiding and penile erections (tumescence). A subsequent high risk of short- and long-term urethroplasty complications, particularly after proximal or long-segment urethral replacement, highlights the need for an improved tissue alternative with a bioinspired design. To create an option for urethral tissue replacement, this proposal addresses key design requirements including 1) optimized scaffold mechanical properties to support cell seeding and early function, 2) structural properties to establish microenvironments supporting primary cell lines and 3) a reproducible scaffold with widely applicable and modifiable fabrication process. The aim of this proposal is the creation of novel tubular biodegradable, biomimetic urethral tissue constructs consisting of multilayered cell sheets that mimic native urethral biomechanical and structural properties. This work will additionally provide key insights into cellular-extracellular matrix interactions and the optimized microenvironment for tissue regeneration.

Project title: Single Cell Spatial Analysis of DLBCL to Develop Biomarkers and Optimize CAR T Therapy

Mentors:

Akil Merchant, MD - Cedars-Sinai Medical Center
Helen Goodridge, PhD - Cedars-Sinai Medical Center
Edwin Posadas, MD - Cedars-Sinai Medical Center
Clive Svendsen, PhD - Cedars-Sinai Medical Center
Simon Gayther, PhD - Cedars-Sinai Medical Center
Yvonne Chen, PhD - UCLA
Joshua Sasine, MD, PhD - Cedars-Sinai Medical Center

Multidisciplinary Expertise:
Nanobiotechnology, Single-Cell Analysis, Microfluidics, Bioinformatics, Materials Science and Engineering

Project Description:
Diffuse Large B-Cell Lymphoma (DLBCL) is the most common non-Hodgkin lymphoma, with high cellular heterogeneity and a significant immune component. DLBCL standard therapy has a failure rate of ~35%, and CAR T-cells are engineered immune cells that have emerged as viable treatments for ~50% of patients that fail standard therapies. New strategies are needed to predict clinical outcomes and improve the efficacy of CAR T therapy. Immune cells in the tumor microenvironment of DLBCL are highly heterogeneous, they have antitumor or pro-tumor properties that affect the clinical outcomes of patients, and they can be conflated with the tumor itself, which expresses immune markers. CAR T cells add yet another moving piece to this intricate puzzle. To resolve this complexity, new technology has emerged to perform spatial analysis of DLBCL at single cell resolution and reveal tumor and immune phenotypes that can act as biomarkers of clinical response. Using Imaging Mass Cytometry (IMC) to analyze 40+ proteins at 1 μm resolution, we can identify tumor-immune spatial relationships in DLBCL, such as local areas of checkpoint expression or infiltrating immune cells. This project’s goal is to use IMC to identify new spatial and protein predictors of clinical outcome, to study CAR T therapy response and its evolution over time, and to test the effects of two CAR T co-treatments on treatment efficacy.

Project title: Harnessing the EHR for the Delivery of Supportive Care in an Oncology Setting

Mentors:

Patricia Ganz, MD – UCLA
Eric Cheng, MD – UCLA
Roshan Bastani, PhD—UCLA

Multidisciplinary Expertise:
Oncology, health services

Project Description:
This project aims to develop and pilot test a supportive care tool within the existing electronic health record (EHR) system, using a structured process based on implementation science principles and methods and training in clinical informatics. The tool will establish linkages between well-validated, easily accessible patient-reported outcome measures for cancer-related symptoms and algorithmic pathways of evidence-based clinical support and defined resources to guide the tailored provision of supportive care. The project will begin with design and development of the tool, followed by pilot testing in the head and neck cancer program in UCLA Health, and culminate with a post-intervention evaluation using a mixed-methods approach. By capitalizing on inherent EHR capabilities and bringing together existing, yet underutilized resources in a user-centered way, this project aims to address gaps in symptom management and supportive care in a multidisciplinary oncology practice.

Project title: Social Support and Health Care Utilization Outcomes in the Subpopulations and Intermediate Outcomes in Chronic Obstructive Pulmonary Disease Study (SPIROMICS) Cohort

Mentors:

Michael Ong, MD, PhD - UCLA
Carol Mangione, MD, MSHS - UCLA
Steven Dubinett, MD – UCLA
Donald Tashkin, MD - UCLA
Jerry Krishnan, MD, PhD – U Illinois at Chicago
Gery Ryan, PhD – Kaiser Permanente & RAND Corporation

Multidisciplinary Expertise:
Chronic obstructive pulmonary disease (COPD), social determinants of health, administrative claims analysis, mixed-methods research, multilevel data modeling

Project Description:
Chronic obstructive pulmonary disease (COPD) is the 4th leading cause of death in the United States and contributes to over $30 billion annually in costs due to health care utilization, primarily due to exacerbations of the disease. An incomplete understanding of the drivers of healthcare utilization have made the development of a patient-centered approach to reduce preventable hospitalizations challenging. This project will use an innovate approach to harmonize biologic, administrative, and interview-derived social context data in an effort to further our understanding of the drivers of exacerbation-related healthcare utilization and identify potential intervention points to reduce burdens on patients and the health care system.

Project title: Mechanisms of Macrophage Memory in Immunity to Staphylococcus aureus Infection

Mentors:

Michael R. Yeaman, PhD. – Lundquist Institute, Harbor-UCLA Medical Center / UCLA
Scott G. Filler, M.D. – Lundquist Institute, Harbor-UCLA Medical Center / UCLA
Matteo Pellegrini – UCLA

Multidisciplinary Expertise:
Infectious disease, microbiology, immunology, innate immune memory, epigenetics, macrophage memory, cell biology, molecular immunology

Project Description:
Staphylococcus aureus (SA) is the leading cause of skin and skin structure infections, which serve as a portal of entry for hematogenous invasion. Treatment for SA infections are complicated by increasing antibiotic resistance. The goal of this project is to discover mechanisms of protective host immune memory to SA infection. We found that host macrophages acquire specific innate immune memory against SA that is transferrable to naïve hosts. This protection is likely mediated by epigenetic modifications. Similarly, bacterial DNA can also undergo epigenetic modifications that mediate pathogenesis. Therefore, this research aims to decipher host vs. bacterial epigenetic mechanisms of immune defense vs. pathogenesis during SA infection. Specifically, we aim to identify macrophage epigenetic signatures that mediate protection, as well as SA epigenetic signatures that facilitate in pathogenesis. Understanding these processes will aid in developing novel anti-infectives and immunotherapies to prevent and treat SA and other multi-drug resistant infections.

Project title: NFκB dynamics in the stimulus specificity of innate immune memory

Mentors:

Alexander Hoffmann, PhD - UCLA
Scott Filler, MD – Lundquist/Harbor-UCLA
Otto Yang, MD - UCLA

Multidisciplinary Expertise:
Molecular biology, innate immunology, bioinformatics, epigenomics

Project Description:
Cytokines and pathogens can reprogram cells of the innate immune system, poising them to be either more inflammatory or less inflammatory, a phenomenon known as innate immune memory. What determines whether a given stimulus will result in potentiated or diminished inflammation is unclear, and the lack of mechanistic insight limits current diagnostic and therapeutic applications of this cellular reprogramming. This proposal explores the hypothesis that dynamic features of the transcription factor NFκB – not if it is activated, but how it is activated – contribute to the stimulus specificity of innate immune memory through the regulation of de novo enhancers that control gene expression. These studies have important implications for understanding how variable and reprogrammable states of the immune system might determine the response to an infection.

Project title: Accelerated biological and phenotypic aging in hematopoietic cell transplant survivors: Social support as a protective factor

Mentors:

Judith Carroll, PhD – UCLA
Julienne Bower, PhD – UCLA
Teresa Seeman, PhD – UCLA
Steve Cole, PhD – UCLA

Multidisciplinary Expertise:
survivorship, clinical psychology

Project Description:
Hematopoietic cell transplantation (HCT) is a widely used treatment for hematologic malignancies; however, many survivors experience late effects that resemble an accelerated aging phenotype, or age-related functional declines thought to be manifestations of aging at the cellular level. Research suggests that HCT can accelerate biological aging by up to 15 years, but not all survivors experience late effects, suggesting that modifiable behavioral factors may influence vulnerability. Given the intense psychological and biological demands of HCT, the recovery period may represent a window of opportunity in which behavioral factors such as social support exert a particular influence. Emerging evidence suggests that social experiences can impact key biological aging pathways in non-cancer populations, but whether they contribute to variability in accelerated aging in HCT recipients has not been tested. This project examines the influence of social experiences on accelerated biological and phenotypic aging in HCT recipients over the first year of recovery.

Project title: Cellular senescence as a driver of progenitor cell dysfunction in progressive pulmonary fibrosis

Mentors:

Barry R. Stripp, PhD – Cedars-Sinai Medical Center

Multidisciplinary Expertise:
Lung Biology, Lung Fibrosis, Acute and chronic lung injury repair, Bioinformatics on omics data.

Project Description:
Idiopathic pulmonary fibrosis (IPF) is an age related progressive interstitial lung disease with a median diagnosis at 66 years old and estimated survival of 2–4 years. Accelerated aging mechanisms including Cellular senescence, are believed to contribute to epithelial progenitor cell dysfunction and progressive tissue remodeling in IPF. However, there has been no systematic analysis of cellular senescence programs that are activated in distinct lung cell types and contribute to tissue remodeling. The goals of current project are to gain fundamental insights into cellular senescent signatures of different lung cell types in human patient samples and mouse models, to understand mechanisms by which epithelial senescence leads to initiation and progression of lung fibrosis and further develop targeting strategy to prevent or reverse disease progression.

Project title: The Urinary Microbiota and Host Inflammation in Lower Urinary Tract Symptoms.

Mentors:

David M. Underhill, PhD – Cedars-Sinai Medical Center
Jennifer T. Anger, MD MPH – Cedars-Sinai Medical Center
Dermot P. McGovern, MD PhD – Cedars-Sinai Medical Center
Suzanne Devkota, PhD – Cedars-Sinai Medical Center
Michael Freeman, PhD – Cedars-Sinai Medical Center

Multidisciplinary Expertise:
female pelvic medicine and reconstructive surgery, patient-reported outcomes, molecular immunology, cell biology, culture-independent microbial profiling, bioinformatics and data science, clinical phenotyping

Project Description:
A growing body of research into storage lower urinary tract symptoms (storage LUTS) -- highly prevalent, debilitating urologic conditions that include overactive bladder and interstitial cystitis/painful bladder syndrome -- suggests a potential role in disease development and progression for the diverse microbial communities of the urinary tract. To explore the pathophysiology of storage LUTS, we will examine the differences in these urinary bacterial and fungal communities and their interactions with host inflammatory responses, including an investigation of potential host genetic susceptibility factors associated with an increased risk of disease. The novel application of large-scale systems biology approaches to the urinary tract and the integration of these data with detailed clinical phenotyping is reshaping our understanding of these syndromes and will facilitate profound advances in the approach to clinical classification as well as the management and treatment of benign urologic conditions.

Project title: Integrative multi-omic hierarchical analysis of undifferentiated pleomorphic sarcoma tissue microenvironment.

Mentors:

Alexander Hoffmann, PhD - UCLA
Albert Thomas, PhD - UCLA
Antoni Ribas, MD, PhD - UCLA

Multidisciplinary Expertise:
systems biology, mathematical modeling, biochemical reaction networks, multi-omic data integration, cross-sectional clinical imaging

Project Description:
Undifferentiated pleomorphic sarcoma (UPS) are tumors that do not all respond to radiation treatment (RT) as expected and this variation is likely attributable, at least in part, due to differences in the populations of immune cells that infiltrate the tumors. We hypothesize that RT affects the metabolic state of the immune cells as well as tumors and that hierarchical measurements provide a means to classify different RT treatment responsive tumors across multiple spatial scales. We will employ a systems approach for metabolic characterization of the multi-cellular interactions in the sarcoma microenvironment using multi-parametric magnetic resonance imaging (mpMRI) in conjunction with high-resolution tissue imaging and multi-omics characterization of cells in order to construct models of metabolism building upon the constraint-based modeling framework. The resulting analyses may provide insights into the different metabolic states of the cells and how different cell populations could be targeted to respond to new drug therapies.

Project title: Treating Ataxia Telangiectasia with Small Molecule Readthrough Compounds.

Mentors:

William (Bill) Boyle, PhD – UCLA
Richard Gatti, MD – UCLA

Multidisciplinary Expertise:
ataxia, neuroscience, drug development

Project Description:
Ataxia telangiectasia (AT) is a rare (~1 in every 100,000), but catastrophic and fatal inherited disease that is caused by a mutation in the ATM gene (AT mutated). No cure or effective treatments exist, therapy consists largely of palliation, and unfortunately, children born with this disease die by the age of ~25 yrs. Up to one third of disease-causing mutations in AT result from a Premature Termination Codon (PTC) in the mRNA encoded by the gene. We seek to demonstrate and develop a new therapeutic directed at overcoming PTCs to treat these AT patients. Our next steps are to screen our current candidate Small Molecule ReadThrough (SMRT) compounds and perform in vivo efficacy testing in a new mouse model of AT that expresses a disease causing PTC.

Project title: Evaluating rurality and gaps in guideline directed care for Veterans with heart failure.

Mentors:

Michael K. Ong, MD, PhD – VA Greater Los Angeles Healthcare System/UCLA
Alison B. Hamilton, PhD, MPH – VA Greater Los Angeles Healthcare System/UCLA
Paul G. Shekelle, MD, PhD – VA Greater Los Angeles Healthcare System/UCLA
Paul A. Heidenreich, MD, MS – VA Palo Alto/Stanford
Donald S. Chang, MD, MPH – VA Greater Los Angeles Healthcare System/UCLA
Gregg C. Fonarow, MD – UCLA

Multidisciplinary Expertise:
Heart failure, quality of care, disparities, performance measurement, telehealth, implementation science

Project Description:
Heart failure is a highly prevalent chronic condition that is the leading cause of hospitalization for adults. A number of evidence-based medical practices improve the quality of life and decrease the risk of premature mortality in patients living with heart failure. Yet, gaps in the receipt of evidence-based, guideline-directed medical therapies (GDMT) remain. The VA is the largest integrated healthcare system in the U.S. and the leading provider of telehealth care. The use of telehealth to improve care for patients with heart failure has not been consistently demonstrated. This pilot project will evaluate how gaps in GDMT might relate to distance from cardiologists and access to care. Veterans living in rural regions of southern California with poor access or barriers to care will be evaluated for receptivity to telehealth visits and health home monitoring. Veterans will be recruited to pilot an intervention to optimize medical therapy for heart failure using established telehealth technologies.

Project title: Multifaceted nanosystems to accelerate the generation and clinical translation of cellular therapies.

Mentors:

Paul S. Weiss, PhD - UCLA
Donald Kohn, MD - UCLA
Ali Khademhosseini, PhD - UCLA

Multidisciplinary Expertise:
Nanoscience, materials science & engineering, materials chemistry, stem cell biology, cellular & gene therapies, pediatric hematology/oncology

Project Description:
We target the design and application of precision-assembled nanostructures that establish controlled and transient permeability of cells to create new tools to enable the broader clinical deployment of gene and cellular therapies. Immunotherapies that utilize T-cells engineered to recognize tumor antigens and to harness the immune system are emerging for these critically ill cancer patients. There is an unmet need for methods capable of processing large populations of these engineered cells quickly, cost effectively, efficiently, and with high recovery rates to generate more homogeneous and better characterized cellular products for clinical translation. Ideas inspired by microfluidics, nanolithography, and nanorobotics are combined with gene editing in this effort to generate broadly applicable and translatable methods for the rapid, efficient, and sustainable introduction of chimeric antigen receptor constructs in combination with gene-editing machinery into human T-cells.

Project title: Targeting radiation-induced myeloid cells in undifferentiated pleomorphic sarcoma.

Mentors:

Antoni Ribas, MD, PhD – UCLA
William McBride, PhD – UCLA
Fritz C. Eilber, MD - UCLA

Multidisciplinary Expertise:
Sarcoma, Radiation Oncology, Tumor Immunology & Immunotherapy, Macrophage and T cell Biology, Translational Clinical Trials, Murine Tumor Models

Project Description:
Up to 50% of patients with soft tissue sarcoma ultimately develop local disease failures or incurable distant metastases despite radiotherapy (RT) and surgery. The central premise of this proposal is that myeloid cells regulate the local and systemic anti-tumor effects of radiotherapy in undifferentiated pleomorphic sarcoma (UPS), a common soft tissue sarcoma. We will utilize both syngeneic murine models of UPS and patient specimens from an ongoing clinical trial to study these phenomena. We propose to characterize RT-induced myeloid cells in UPS and their impact on (1) local tumor control and (2) systemic anti-tumor T cell responses. Our approach will include high-dimensional cytometry, single cell proteomics, and multiple strategies to target myeloid subsets in combination with focal RT in murine models. We envision these studies will inform design of a clinical strategy to target myeloid subsets in combination with RT to improve local control, reduce metastases, and prolong survival.

Project title: Implementation and clinical effectiveness of cervical cancer prevention in Malawi: A critical evaluation to bring screening and treatment to scale.

Mentors:

Roshan Bastani, PhD – UCLA
Judith Currier, MD MSc – UCLA
Dr. Beth Glenn, PhD – UCLA

Multidisciplinary Expertise:
Implementation science, clinical outcomes research, cancer prevention and control

Project Description:
There is a vast and growing burden of non-communicable diseases in low-income countries, but little rigorous research about implementing and scaling-up effective strategies. Breakthroughs in clinical and translational science require accompanying implementation research to understand the real-world “how and why” of uptake and outcomes. Malawi has the highest rates of cervical cancer incidence and attributable mortality in the world; and, as in many low-resource settings, women typically present with advanced disease because they do not have access to cervical cancer screening. This research will use implementation science methods to identify strategies for reducing the excess burden of cervical cancer among women in Malawi. It will apply qualitative, quantitative and modeling methods in new ways to understand the implementation and effectiveness of cancer care delivery in this resource-limited health system. This project will build on a longstanding collaboration between UCLA and a Malawian health care organization, Partners in Hope.

Project title: Targeting ferroptosis in resistant melanoma.

Mentor:

Tomas Ganz, PhD, MD – UCLA

Multidisciplinary Expertise:
Iron metabolism, cancer metabolism, animal models, bioinformatics, clinical hematology/oncology

Project Description:
New treatments are required for patients with metastatic melanoma that have progressed after MAPK pathway inhibition and immune therapies. Melanoma can evade these therapies through dedifferentiation. This process, which resembles epithelial-to-mesenchymal transition in carcinomas, is characterized by transcriptional reprogramming. Bioinformatic interrogation of a melanoma dedifferentiation signature in a large publicly-available pharmacogenomics database led to the discovery of a subtype-specific susceptibility to ferroptosis-inducing agents. This project aims to validate this computational lead, establish the in vivo efficacy of ferroptosis drugs, and study the mechanistic basis of ferroptosis in dedifferentiated melanomas.

Project title: Syndecan-1 Regulation of Lung Fibrosis.

Mentors:

Peter Chen, MD – Cedars-Sinai Medical Center
Cory Hogaboam, PhD – Cedars-Sinai Medical Center

Multidisciplinary Expertise:
Lung Biology, Exosome Biology, Lung Fibrosis

Project Description:
Idiopathic pulmonary fibrosis (IPF) is a fatal progressive lung disease. The overarching concept of IPF pathogenesis is that epithelial damage and dysregulated epithelial repair leads to perturbations of the lung microenvironment that induce various fibrogenic signals to recruit and activate various effector cells causing fibroproliferation. The critical knowledge gap in this paradigm is how epithelial dysfunction produces signals that coordinate effector cells in the pathogenic process. Syndecan-1 is primarily expressed by epithelial cells. Aberrancy of syndecan-1 expression leads to dysregulation of tissue repair. We found that syndecan-1 is overexpressed by the lung epithelium in IPF. We also demonstrated that syndecan-1 is pro-fibrotic in a murine bleomycin-injury model. Moreover, deviations to normal syndecan-1 expression levels promote lung fibrosis by altering miRNAs packaging in exosomes. The current project is to study the mechanisms by which syndecan-1 regulates miRNA loading into exosomes and to determine how syndecan-1 promotes fibrosis through exosomal miRNAs.

Project title: Outcomes and Mechanisms of Bidirectional EphB/ephrinB2 Decoupling in Multiple Myeloma.

Mentors:

John Chute, MD - UCLA
Ken Dorshkind, PhD - UCLA

Multidisciplinary Expertise:
Cancer biology, malignant microenvironment, stem cell regulation, hematopoietic cell transplant, chimeric antigen receptor (CAR) T-cells, clinical hematology-oncology

Project Description:
Multiple myeloma (MM) is the most common primary bone marrow malignancy and, despite advances in treatment, remains incurable. It resides almost exclusively in the bone marrow. Interactions between MM and the bone marrow microenvironment are essential for disease progression but the details of those interactions are not well understood. Bone marrow vascular endothelial cells (BMECs) strongly support myeloma and we hypothesized that this was due to a paracrine effect. Using tissue-specific endothelial cell screens and siRNA screens, we saw that the EphB/ephrinB signaling promoted MM through BMECs. EphB and ephrinB are cell surface tyrosine kinase receptors which initiate bidirectional signaling events in cells upon engagement. Loss of ephrinB2 in MM severely impaired MM growth in vivo. We will further examine the consequences of decoupling EphB/ephrinB2, evaluate the downstream molecular pathways responsible for this effect, and determine if this is a path to a pharmacologically tractable intervention.

Project title: The Impact of a Medical-Financial Partnership on Parent Health-Related Quality of Life and Child Developmental Risk Among Low-Income Families: A Randomized Controlled Trial.

Mentors:

Peter Szilagyi, MD, MPH - UCLA
Paul Chung, MD, MS - UCLA
Kenneth Wells, MD, MPH - UCLA
Doug Jutte, MD, MPH – UC Berkeley
Geri Ryan, PhD – RAND

Multidisciplinary Expertise:
Social Determinants of Health, Primary Care Clinical Redesign, Pediatric Health Services Research, Implementation Science

Project Description:
Poverty is a dominant driver of population health and health systems are increasingly addressing social determinants of health and social needs, such as food insecurity, housing insecurity, and other symptoms of financial hardship. Financial coaching is a standardized approach to improving family financial health through motivational interviewing and financial education, which has been proven to increase savings and reduce debt in low-income households. Our study will test whether there are health benefits to low-income families of addressing their financial hardship directly by providing them with financial coaching in addition to social needs navigation in a primary pediatric clinic. We will develop scalable approaches to clinical implementation of financial coaching and examine its effects on parent health-related quality of life, child developmental risk, and primary care utilization. Our study will inform the growing field of medical-financial partnerships through a national learning network of clinicians and financial capabilities professionals.

Project title: Understanding the mechanism of lentivector-based immunization.

Mentor:

Jerome A. Zack, PhD - UCLA

Multidisciplinary Expertise:
Immunology, Innate immunity, Virology, Signaling Transduction, Vaccines

Project Description:
Dendritic cells (DCs) are critical to stimulating adaptive immune responses owing to their superior ability to process antigens and present them to T cells. Methods have been devised to directly target antigen to DCs for immunization purposes. One effective strategy uses an HIV-1-derived lentiviral vector (LV) to deliver genes encoding antigen to DCs. The in vivo administration of this vector results in the selective expression of antigen in DCs and efficient priming of antigen-specific CD8+ T cells. However, the exact mechanism behind such efficient immunization is not clear. In this project we seek to understand how LVs perform two independent functions: delivery of antigen and activation of DCs. We expect to identify the mechanisms of LV antigen delivery, the immunostimulatory LV components and corresponding host innate immune signaling pathways. In addition, our findings will raise important questions regarding the nature of particles in vector preparations and discovery of novel immune agonists for vaccination.

Project title: Leveraging Electronic Health Records to Develop the Next Generation of Quality Measures: eMeasures of Low Value Care

Mentors:

Catherine Sarkisian, MD, MSPH - UCLA
Cheryl Damberg, PhD - RAND Corporation

Multidisciplinary Expertise:
Quality Measurement and Improvement, Appropriateness of Care, Electronic Health Records.

Project Description:
This project seeks to develop electronic health record-based measures of low value care (“eMeasures”), which will be critical for ongoing efforts to improve the quality and value of U.S. healthcare delivery. The work will also evaluate important correlates of low value care, which will help inform future interventions aiming to safely reduce wasteful spending and prevent patient harm from unnecessary care. The long-term goal of the project is to leverage electronic health records in order to build a new generation of low value care eMeasures, which ultimately become the prototype for a new national standard of quality measurement.

Project title: The role of sodium-dependent glucose transport in early-stage lung adenocarcinoma: diagnostic and therapeutic implications

Mentors:

Steven Dubinett, MD - UCLA
David Shackelford, PhD - UCLA
Jorge Barrio, PhD - UCLA
Ernest Wright, PhD - UCLA
Thomas Graeber, PhD - UCLA
Dean Wallace, MD - UCLA
David Elashoff, PhD - UCLA

Multidisciplinary Expertise:
PET Imaging, Oncology, Cancer Metabolism, Translational Research, Pre-clinical Trials in Mouse Models, Lung Pathology, Lung Carcinogenesis.

Project Description:
My project is focused on the role of sodium-dependent glucose transporter 2 (SGLT2) in early-stage lung adenocarcinoma. SGLT2 functions independently of the widely described glucose transporter (GLUT) system, and represents a previously unknown means for malignant cells to sustain their increased need for glucose. My preliminary studies have shown that SGLT2 is expressed in pre-neoplastic and early-stage lung adenocarcinoma (LADC). This is important because high-resolution computed tomography (CT) is very sensitive in detecting early-stage, asymptomatic lung lesions, but it is not specific and cannot distinguish between benign and malignant lesions. Positron-emission tomography (PET) with 2-[F] fluoro-2-deoxyglucose (F-FDG), which detects GLUT activity, is used to stage advanced ADC, but cannot effectively detect early lesions; however, F-FDG does not measure SGLT activity. To study SGLT-mediated glucose transport in pre-malignancy and early-stage lung adenocarcinoma, we use a radio-labeled positron emission tomography (PET) probe, methyl-4-[F] fluorodeoxyglucose (F-Me4FDG), specific for SGLTs. This novel tracer has the potential to complement F-FDG in the diagnosis of early-stage lung tumors. In addition, F-Me4FDG PET can be used to identify SGLT2-active tumors, which may be targeted using FDA-approved SGLT2 inhibitors, the gliflozins. I am going to carry on a pre-clinical validation of F-Me4FDG PET as a translational imaging-based platform to non-invasively identify pre-malignancy and early-stage SGLT2-active lung tumors likely to benefit from treatment with gliflozins.

Project title: Development of a novel platform for the discovery of antigen specific TCRs

Mentors:

Dr. Gay Crooks - UCLA
Dr. Owen Witte - UCLA

Multidisciplinary Expertise:
Immunology, stem cell biology, cancer immunotherapy, cellular therapy, clinical hematology/oncology.

Project Description:
Engineered T cell immunotherapies offer unprecedented potential in the treatment of cancer. Identification of high-affinity T cell receptors (TCRs) that recognize public tumor-associated antigens (TAAs) may facilitate the rapid development of new T cell therapies for cancer. Identification of these TCRs from patient samples however is difficult, as TAA-reactive T cells are typically deleted in the thymus through negative selection. We have developed a novel artificial thymic organoid (ATO) system that permits the efficient in vitro generation of T cells from human hematopoietic stem cells. We hypothesize that T cells generated in ATOs are not subject to conventional negative selection and are thus a unique source of high-affinity TAA-reactive TCRs. In this project, I will optimize an ATO-based platform for the discovery of TCRs specific for model public tumor antigens; characterize the binding affinity and anti-tumor efficacy of ATO-derived TCRs; and validate this system through the proof-of-concept capture of TCRs against clinically relevant TAAs for which the isolation of high-affinity TCRs has been challenging. A platform for the rapid identification of high-affinity TAA-reactive TCRs would be readily translatable to clinical applications in cancer immunotherapy.

Project title: Role of EGF Receptor in TLR7-mediated Glomerulonephritis

Mentors:

Moshe Arditi, MD - Cedars-Sinai Medical Center
David M. Engman, MD, PhD - Cedars-Sinai Medical Center

Multidisciplinary Expertise:
Glomerulonephritis, Toll-like receptor (TLR) signaling, Epidermal Growth Factor Receptor (EGFR), innate immunity, Nephrology, Renal pathology,

Project Description:
Glomerulonephritis (GN) is a group of inflammatory diseases in kidney glomeruli, a filtering system for blood to generate urine. GN is associated with significant morbidity and mortality, and is highly prevalent: it affects 0.12% of the general population and 1.2% of the older population, and often results in dialysis-requiring end-stage renal disease, hospitalization, or death. Epidermal Growth Factor Receptor (EGFR), a receptor tyrosine kinase, is necessary for a rapidly progressive malignant form of GN. We will investigate the critical signaling pathway for GN at the molecular and functional levels using a cell culture system, dissect the pathomechanism of GN and study the therapeutic application of substances that inhibit EGFR in a mouse model of malignant GN. To translate this work into a potential treatment for humans, we will seek to identify the subtypes of human GN that could be good candidates for EGFR inhibitor therapy using kidney biopsy samples.

Project title: Using Systems Biology Approaches to Combat the Evolution of Multi-Drug Resistant Pathogens

Mentors:

Robert Damoiseaux, PhD, UCLA
Harvey Herschman, PhD, UCLA
Barbara Natterson-Horowitz, MD, UCLA

Multidisciplinary Expertise:
Experimental Evolution, Microbial Ecology, Systems Biology, Antibiotic Resistance, Multiple Stressors, Drug Interactions, Emergent Properties, Higher-order Interactions.

Project Description:
The evolution of multi-drug resistant pathogens is an urgent and growing global health issue. Here we tackle the challenge of antibiotic resistance in three ways, combining evolutionary perspectives and systems biology concepts with high throughput experimental capabilities. First, we investigate how antibiotics that are typically only used in gram-positive bacteria can be effectively used as novel treatments in gram-negative bacteria via synergy with other drugs. Second, we examine higher-order interactions that occur among more than two-drug combinations in order to discover and determine synergistic and antagonistic interactions to employ against pathogens. Finally, we will determine mechanisms of action and mechanisms of synergy using mutagen-antibiotic combinations. Our overarching goal is to find novel methods and treatment strategies to combat the evolution of drug-resistant bacteria.

Project title: The Effect of Nanoparticle-Encapsulated Resveratrol for Treatment of Periodontitis.

Mentors:

Cun-Yu Wang, DDS, PhD – UCLA
Ben Wu, DMD, PhD – UCLA

Multidisciplinary Expertise:
Molecular biology, bone biology, bioengineering

Project Description:
Periodontitis is the most common osteolytic disease that afflicts approximately 50% of the population over the age of 30. Aside from destruction to local periodontal tissue and loss of tooth support, periodontitis is also a risk factor for many systemic diseases such as diabetes, cardiovascular diseases and oral cancer. Unlike the conventional treatment that focuses on removal of pathogens, this project aims to develop a novel approach using reseveratrol (grape extract)-loaded nanoparticles locally placed under the gum line to target periodontal inflammation, the actual mediating mechanism underlying periodontal tissue destruction. The study will investigate if reseveratrol will inhibit bone resorption and inflammation via upregulation of PGC-1α gene; the efficacy and safety of nanoparticles will also be evaluated in a murine model.

Project title: Promoting Access to Behavioral Health Services for Youth Transitioning Home After Incarceration

Mentors:

Paul Chung, MD, MS - UCLA
Laura Abrams, PhD - UCLA
Bonnie Zima, MD, MPH

Multidisciplinary Expertise:
Juvenile Justice, General Pediatrics, Behavioral Health, Community-Partnered Research

Project Description:
This project explores youths’ access to community-based behavioral health services during reentry, the vulnerable period following a youth’s release from juvenile incarceration. Up to 70% of incarcerated youth have at least one behavioral health disorder. These disorders increase future incarceration risk, and incarceration and reentry likely have negative effects on behavioral health. Despite the existence of effective, evidence-based behavioral health programs tailored for these youth, reentry youth are at enormous risk for poor health, education, and employment outcomes, and typically experience poor access to community-based behavioral health services. During Phase I, we will use a mixed methods approach to describe youth and parent perspectives on reentry youths’ behavioral health needs and access to community-based behavioral services. During Phase II, we will engage community stakeholders to develop and pilot test a family-centered intervention, such as a transitions life coach intervention, to promote youths’ access to community-based behavioral health services during reentry.

Project title: Dissecting the function of Myc paralogs in human prostate cancer

Mentors:

Owen Witte, MD - UCLA

Collaborators:

James Wohlschlegel, PhD – UCLA
Justin Drake, PhD – Rutgers
Josh Stuart, PhD – UC Santa Cruz

Multidisciplinary Expertise:
Cancer biology, proteomics, genomics/transcriptomics, functional genetic screening

Project Description:
Myc proteins are multi-functional transcription factors whose deregulation is central to the initiation and maintenance of most human cancers. They are broadly thought to have redundant functions in development and tumorigenesis. In prostate cancer, the amplification and overexpression of c-Myc are common in prostate adenocarcinomas while N-Myc is amplified and overexpressed in 40% of neuroendocrine prostate cancers (NEPC). Prior work using a tissue recombination assay has shown that ectopic expression of c-Myc and activated AKT1 in human prostate epithelial cells produces poorly differentiated adenocarcinoma and squamous cell carcinoma while N-Myc and activated AKT1 generates mixed NEPC and prostate adenocarcinoma. These findings indicate that Myc paralogs may drive the pathogenesis of discrete cancer phenotypes through distinct biologic functions mediated by their regulatory complexes. The objective of this work is to characterize the core and divergent functions of c-Myc and N-Myc in prostate cancer through interactome, transcriptome, proteome, phosphoproteome, and functional analyses.

Project title: The Role of Neutophil Activation in Hepatic Ischemia-Reperfusion Injury

Mentors:

Jerzy Kupiec-Weglinski, MD, PhD – UCLA
Steven Bensinger, DVM, PhD – UCLA

Multidisciplinary Expertise:
Liver Transplantation, Liver Disease, Inflammation, Neutrophils, Cytokines, Cell and Molecular Biology, Signal Transduction, Ischemia-Reperfusion Injury

Project Description:
Ischemia/reperfusion injury is the principal mechanism of organ damage in transplantation, heart attacks, strokes, and other vascular diseases. It is a multifactorial inflammatory process that occurs without any exogenous antigens and instigates a series of innate immune-related responses that can result in cell damage, cell death, and organ failure. Neutrophil activation is a major effector cell in ischemia/reperfusion injury. Our proposal probes the connections between a key signaling molecule, Bruton’s tyrosine kinase, and the activation of neutrophils, as well as how these interactions and their effects lead to liver ischemia/reperfusion injury. We intend to do this using a murine model, as well as by studying specimens obtained at the time of surgery from human liver transplant recipients. By understanding the mechanisms through which the activation of neutrophils can be inhibited or modified, we can derive new therapies to prevent or treat ischemia/reperfusion injury.

Project title: A Predictive Model for Pediatric Parenteral Nutrition Associated Cholestasis Using Novel Biomarkers: Plasma Phytosterols, Cytokines, and Bile Acids and Erythrocyte Omega-6:Omega-3 Ratios

Mentors:

Sherin Devaskar, MD – UCLA
David Elashoff, PhD – UCLA

Multidisciplinary Expertise:
Pediatrics, hepatology, nutrition and metabolism, biomarker discovery, biomathematics

Project Description:
Parenteral nutrition (or intravenous nutrition) is associated with a potentially lethal liver disease—parenteral nutrition associated cholestasis (PNAC). Neonates are highly susceptible to PNAC. Liver biopsies and serum direct bilirubin are standard tests for PNAC diagnosis, but they have limitations. There is a need to develop leading biomarkers as diagnostic tools that reflect early liver injury. I have supporting evidence that high concentrations of phytosterols, omega-6:omega-3 fatty acid ratios, and cytokines impede biliary flow, resulting in an increase in bile acids. In a cohort of infants at high risk for PNAC, I will: 1.) assess changes in these biomarkers over time, and 2.) determine if a profile of biomarkers in combination with clinical risk factors can predict PNAC. Should my hypothesis be correct, a biomarker profile could be used pro-actively to sub-select patients at high risk for PNAC so that therapeutic modalities could begin in a timely manner.

Project title: Impact of Hepatitis C Co-infection on Cardiovascular Risk in HIV-infected Persons

Mentors:

Judith S. Currier, MD, MSc – UCLA
Debika Bhattacharya, MD, MS – UCLA
Raymond T. Chung, MD – Harvard Medical School, Massachusetts General Hospital
David Elashoff, PhD – UCLA
C. Noel Bairey Merz, MD – Cedars-Sinai Medical Center
Steven-Huy Han, MD – UCLA

Multidisciplinary Expertise:
Infectious disease, cardiovascular disease, liver disease, inflammation

Project Description:
In the current era of effective antiretroviral therapy (ART) and aging HIV-infected patients, cardiovascular disease (CVD) and other non-AIDS complications are responsible for an increasing number of deaths. CVD risk is increased in HIV-monoinfected persons and HCV coinfection, as a second chronic viral infection with associated immune activation and inflammation, as well as known metabolic derangements, may further increase this risk. The proposed study will establish a multi-site prospective, longitudinal cohort of sociodemographically diverse HIV/HCV-coinfected and matched HIV-monoinfected men and women with HIV suppressed on stable ART to investigate the impact of HCV coinfection on CVD risk assessed by endothelial function and soluble CVD biomarkers and the potential for HCV treatment to improve CVD outcomes, as well as explore macrophage activation as a mediator of endothelial dysfunction in HIV/HCV.

Project title: Dendritic Cell Vaccination for Newly Diagnosed Pediatric High-Grade Glioma Patients

Mentors:

Linda Liau, MD, PhD - UCLA
Robert Prins, PhD - UCLA

Multidisciplinary Expertise:
Pediatrics, Hematology-Oncology, Neuro-Oncology, Tumor Immunology, Translational Cancer Research, Immunotherapy, Clinical Trials.

Project Description:
Brain tumors in the pediatric population have poor prognosis and account for the highest mortality rate of all childhood cancers. High grade gliomas (HGG) remain the biggest challenge, with few treatment options and an overall 5-year survival rate of 10-30%. A potential alternative to conventional treatments is utilizing a patient’s own immune system to target and eliminate tumor cells. In this study, dendritic cells (DC) isolated from the subject's own blood will be co-cultured with tumor lysate. These stimulated DCs will then be injected back into the patient as a vaccine in order to teach the host immune system to “recognize” the malignant brain tumor cells as “foreign” to the body. We propose that this will help instruct the patient’s own immune system to attack any residual tumor cells. We hypothesize that DC vaccination for pediatric HGG patients will induce better outcomes than current standard therapies with chemotherapeutics and radiation alone.

Project title: Mechanistic Study of Combined Targeted Therapy and Immunotheray for Melanoma

Mentors:

Antoni Ribas, MD, PhD – UCLA
John Glaspy, MD, MPH – UCLA
Steven Dubinett, MD – UCLA

Multidisciplinary Expertise:
Tumor Immunology, Translational Cancer Research, Cell and Molecular Biology, Signaling Transduction, Clinical Trials.

Project Description:
Recent breakthrough of immune checkpoint inhibition has resulted in durable disease control of metastatic cancers in a small subset of patients, and BRAF and MEK inhibitors can induce highly frequent tumor responses in patients with BRAFV600E mutant melanoma, but of limited durability. BRAF and MEK inhibitors can sensitize the immune system to target tumors, providing the rationale to synergize with immunotherapy for durable response in majority of patients. Our pre-clinical studies using syngeneic BRAFV600E mutant melanoma mouse model showed significantly improved antitumor effect combining BRAF inhibitor dabrafenib and MEK inhibitor trametinib, with either pmel-1 adoptive cell transfer or anti-PD1 immunotherapy, with increased tumor infiltrating lymphocyte, preserved effector function, and favorable changes in the tumor milieu. Based on these results, three Phase I trials have been opened at UCLA testing the combination of BRAF and MEK inhibitors with anti-PD-1/L1 antibodies. I proposed to study the clinical relevance of the preclinical findings in paired pre- and post-dosing biopsies that we have been collecting in these trials.

Project title: A MICU Sleep Promotion Intervention Using Actigraphic Outcome Assessment

Mentors:

Michael Ong, MD, PhD – UCLA
Jennifer Martin, PhD – UCLA
Dale Needham, MD, PhD – Johns Hopkins University
Nancy Collop, MD – Emory University

Multidisciplinary Expertise:
Quality Improvement, Actigraphy, ICU Outcomes, Sleep in the ICU, Implementation Methods.

Project Description:
Poor sleep is common in the intensive care unit (ICU) and is felt to contribute to adverse patient outcomes, including delirium. To address this problem, we will implement a sleep promoting intervention in the RRUMC medical ICU (MICU). Using an established, multi-disciplinary approach, and a before-after study design, this intervention will involve three incremental sleep improvement Stages: 1) environmental interventions (minimization of noise, light, and patient disturbances); 2) non-pharmacologic interventions (earplugs, eye masks, soothing music), and 3) a guideline promoting use of appropriate pharmacologic sleep aids. This study aims to extend a prior improvement effort into a new hospital system, and to evaluate its effect on delirium and actigraphic estimates of sleep. The use of actigraphy, a wristwatch-like accelerometer device used to assess activity and sleep, represents a novel application of an established research tool, and poses a practical option for sleep estimation during this and future ICU intervention efforts.

Project title: Regulation of myeloid cell development during cutaneous immune responses

Mentors:

Robert Modlin, MD – UCLA
Maria Ochoa, MD – UCLA
Steven Dubinett, MD – UCLA
Harvey Herschman, PhD – UCLA
Matteo Pellegrini, PhD – UCLA
David Elashoff, PhD - UCLA

Multidisciplinary Expertise:
Immunology, host defense, type I interferon, skin immunity, infection

Project Description:
Leprosy is a human skin disease caused by the bacteria Mycobacterium leprae (mLEP) that presents with a range of clinical systems that correlate with the immune response to the bacteria making it an ideal model to study skin immunity. The goal of this proposal is to determine mechanisms by which developing myeloid cells can be polarized into various effector cells by factors identified in the skin of leprosy patients. Preliminary data identifies, IL-34, as a potential factor contributing to polarization into a suppressive phenotype, as it is increased in skin lesions from the progressive form of leprosy (L-lep) compared to the self-limiting or tuberculoid form (T-lep). IL-34 can drive IL-10 production in early Tie-2 expressing progenitors and monocytes upon mLEP stimulation. Studying mechanisms leading to differences in the two forms of leprosy has the potential to lead to novel therapies for cutaneous inflammatory diseases.

Project title: Determination of Single-Cell Heterogeneity of Circulating Tumor Cells in Cancer

Mentors:

Matthew Rettig, MD – UCLA
Dino Di Carlo, PhD – UCLA
David Elashoff, PhD – UCLA

Multidisciplinary Expertise:
Cancer, Metastasis, Circulating Tumor Cells, genomics/transcriptomics, bioengineering

Project Description:
Cancer can pose a significant burden when in advanced stages or recurrent; the Vortex Chip technology that we have developed provides a non-invasive method to collect circulating tumor cells (CTCs) and can serve as a source of cells to study tumor cell heterogeneity. Understanding heterogeneity in cancer, particularly at the single cell level, will be important in understanding tumor evolution and in predicting response to treatments and this work aims to examine single cell heterogeneity through capture of CTCs from patients with advanced cancer and to validate its use for determining molecular and genetic information. Such information will allow for improved understanding of cancer and may assist in development of more specifically targeted treatments.

Project title: Extinction Learning as Facilitator of Cognitive Bias Modification for Youth Anxiety

Mentors:

John Piacentini, PhD – UCLA
Michelle Craske, PhD – UCLA

Multidisciplinary Expertise:
Anxiety disorders, child and adolescent psychology, experimental therapeutics, fear learning

Project Description:
Anxiety is a chronic and debilitating condition that affects up to 30% of youth. As anxious individuals interpret ambiguous information as threatening, researchers have begun to directly modify interpretation with the use of computerized cognitive bias modification interventions (CBM-I), which are proposed to reduce anxiety by training more benign, rather than threatening, cognitive associations. The current study involves a randomized controlled trial of CBM-I, as compared to a computerized control condition, to treat youth anxiety and simultaneously test whether the intervention works by extinguishing cognitive fear associations. Anxious youth (ages 10 to 17) will be randomly assigned to 12 sessions of either a personalized CBM-I program or a computerized control condition. Anxiety, interpretation bias, and physiological arousal during a fear paradigm will be assessed at pre-, mid-, and post-treatment to explore extinction learning as a putative mechanism underlying CBM-I efficacy. Findings have immediate clinical implications for potential use of CBM-I as stand-alone intervention, as well as an augmentation to exposure-based therapy.

Project title: Chemical Genomics Screen to identify Inhibitors of Candida albicans biofilm

Mentors:

Ashraf Ibrahim, Ph.D – Lundquist/Harbor-UCLA
John E. Edwards, MD – Lundquist/Harbor-UCLA
Robert Damoiseaux, PhD – UCLA

Multidisciplinary Expertise:
Infectious diseases, Chemical genomics, Drug development

Project Description:
The fungus Candida albicans is the third leading cause of intravascular catheter-related infections, most of which are due to the presence of biofilms in these devices. Cells in biofilms display high levels of resistance to most antifungal agents and prolong infections by providing a safe sanctuary from which organisms can seed new infection sites. Thus, dispersal of cells from biofilms becomes a significant phenomenon, predisposing susceptible patients to life threatening disseminated candidiasis. The goal of this proposal is to inhibit the process of biofilm dispersal by screening hundreds of FDA approved small molecule drugs, in novel, high-throughput biofilm assays. Short-listed molecules will be validated in a unique catheterized mouse model of biofilm formation, for their potency to inhibit biofilm-associated dissemination in vivo. Overall, this study will provide novel drug candidates that will supplement the rapidly shrinking antifungal-drug armory against C. albicans biofilms.

Project title: Novel Antibacterial Coatings Preventing Implant Infections

Mentors:

John Adams, MD – UCLA
Jeff Miller, PhD – UCLA
Moshe Arditi, MD – Cedars–Sinai Medical Center
George Liu, MD – Cedars–Sinai Medical Center
Lloyd Miller, MD, PhD – Johns Hopkins Medicine

Multidisciplinary Expertise:
Inflammation, Infectious Disease, Orthopaedic Surgery, Bioengineering, Immunology

Project Description:
Implant infection after orthopaedic surgery is devastating to patients, leading to multiple reoperations and increased morbidity and mortality. These infections are also an enormous burden to our health system, comprising more than $8 billion in additional health care spending. This project will explore novel antimicrobial coatings aimed at reducing the incidence and virulence of implant infection. We will utilize a novel mouse model of orthopaedic implant infection to assess in vivo efficacy and safety of these coatings and analyze effects on osseointegration. We will also examine the mechanism of bacterial evasion of antimicrobial effects. In sum, this project will provide the groundwork for developing an effective, well-tolerated antimicrobial coating ready for large animal study and/or human clinical trial.

Project title: Sleep Loss as a Vulnerability Factor for Inflammation-Induced Depressive Symptoms in Older Women

Mentors:

Michael Irwin, MD - UCLA
Steve Cole, PhD - UCLA
Naomi Eisenberger - UCLA

Multidisciplinary Expertise:
Psychoneuroimmunology, sleep disturbance, depression, fatigue, aging research, epidemiology

Project Description
Sleep disturbance and depression in older adults – especially in older women – are major public health burdens because both conditions are highly prevalent and associated with morbidity, functional decline, and mortality. Although the association between these two conditions is well known, the mechanisms of this association are poorly understood. Dr. Cho’s project aims to examine the potential causal contribution of sleep loss to depressive symptoms via inflammatory mechanisms in older women, by means of experimentally induced sleep deprivation and systemic inflammation. Specifically, it is hypothesized that sleep loss is a vulnerability factor for inflammation-induced depressive symptoms in older women, and this hypothesis will be examined by partial sleep deprivation followed by endotoxin challenge. The findings of this study may guide future clinical studies in identifying individuals at risk of developing depression when exposed to heightened inflammatory states such as aging, obesity, and chronic disease and also in developing prevention strategies for late-life depression.

Project title: Biological Pacemaker in a Pre-Clinical Model of Heart Block

Mentors:

Eduardo Marb?n, MD, PhD - Cedars-Sinai Medical Center
Sumeet Chugh, MD - Cedars-Sinai Medical Center
Hee Cheol Cho, PhD - Cedars-Sinai Medical Center

Multidisciplinary Expertise:
Cellular biology, molecular biology, gene therapy, cellular electrophysiology, clinical cardiac electrophysiology, cellular mechanisms of arrhythmias

Project Description
Abnormally slow heart rhythms affect many people in the USA, and those numbers are steadily increasing as the population ages. While electronic pacemakers are the mainstay of therapy for these conditions, complications from device implantation, such as life-threatening infections, may occur. As an alternative to electronic devices, we propose to study select biological pacemaker candidates in a pre-clinical model, and to develop the most promising candidate as a potential therapeutic agent for first-in-human application.

Gene-based BioP were first described more than a decade ago; somatic gene transfer of various constructs has shown to create BioP activity. However, until recently, in-vivo preclinical applications have been mostly limited to highly-invasive open-chest models. We have developed a clinically-realistic minimally-invasive delivery technique and used it to create BioP in a porcine model of complete heart block. We propose to use this approach to compare two “finalist” therapeutic candidates with fundamentally different mechanisms of action.

Project title: An innovative approach to the preserve peritoneal membrane

Mentors:

Sharon Adler, MD – Lundquist/Harbor-UCLA
Isidro Salusky, MD – UCLA
Cynthia Nast, MD – Cedars-Sinai Medical Center
Youngju Pak, PhD – Lundquist/Harbor-UCLA

Multidisciplinary Expertise:
Nephrology, pathology, pharmacodynamic methodology, cell and molecular biology and biostatistics

Project Description
Peritoneal dialysis (PD) is more cost-efficient and offers a better quality of life than hemodialysis (HD) for patients with end stage renal disease, but long-term utilization is limited by membrane failure. The standard osmotic agent that drives fluid removal in PD is dextrose, which is one of the most important causes of long-term peritoneal membrane injury and functional loss. Although a maltose polymer (icodextrin) improves fluid removal, it does not improve actual dialysis, nor has it reduced inflammation. Our preliminary data from cell cultures, animal studies and human PD effluent has implicated JAK/STAT signaling in PD fluid-induced peritoneal inflammation and injury. This proposal will test whether JAK/STAT inhibition preserves peritoneal membrane structure and function in rats and inhibits inflammation in patients. Together, these data may provide support for Phase 2 testing in PD patients.

Project title: Understanding Inappropriate Treatment in Critically Ill Patients

Mentors:

Neil Wenger, MD, MPH – UCLA
Derjung Mimi Tarn, MD, PhD - UCLA
Chi-Hong Tseng, PhD – UCLA
Eric Kleerup, MD - UCLA

Multidisciplinary Expertise:
Critical care, pulmonary medicine, ethics, and end-of-life research

Project Description
Advances in medicine have enabled the ICU to save lives as well as prolong the dying process. Inappropriate treatment, defined here as a treatment that should not be provided because it does not offer the patient benefit, can prolong suffering, cause family distress, damage the healthcare team morale, and transform death into an undignified process. In this proposal, Dr. Neville aims to characterize the patient, clinical, and communication factors that are related to the provision of inappropriate treatment in the ICU and arrive at an empirical definition. The empirical definition will be validated and used to generate a model to prospectively identify patients at risk of receiving futile treatment. Understanding of the factors leading to provision of such care will advance the field by providing a foundation for intervention.

Project title: Racial and Ethnic Differences in the Initiation of Peritoneal Dialysis

Mentors:

Keith Norris, MD – UCLA
Gery Ryan, PhD – RAND
Sharon Adler, MD – Lundquist/Harbor-UCLA

Multidisciplinary Expertise:
Nephrology, clinical outcomes, disparities research, health services research, pharmacoepidemiology

Project Description
Dialysis is a life-saving procedure for Americans with end-stage kidney disease. The most common modalities are hemodialysis (HD), which is generally performed in a dialysis unit by trained personnel, and peritoneal dialysis (PD), which is usually carried out at home by the patient. PD has been systematically underutilized in the U.S., particularly among black and Hispanic patients. This has significant implications since the modalities can affect patients’ lives quite differently. This project will explore racial and ethnic differences in the initiation of PD. We will first quantify the variation in PD use across racial and ethnic groups, then use qualitative research methods to explore why such variation exists. Finally, we will translate these results into a culturally competent group-based intervention that will educate patients about their modality choices. This will help ensure that patients of all racial and ethnic backgrounds have equal access to every type of dialysis care

Project title: Gene expression profiles of ECT response in Major Depressive Disorder

Mentors:

Nelson Freimer, MD – UCLA
Katherine Narr, PhD – UCLA
Randall Espinoza, MD, MPH – UCLA
Giovanni Coppola, MD – UCLA

Multidisciplinary Expertise:
Neurocognitive phenotyping, neuroimaging, neuropsychiatric genetics, gene expression, biopsychology

Project Description:
Dr. Congdon’s research project is aimed at identifying gene expression profiles of electroconvulsive therapy (ECT) response in patients with Major Depressive Disorder (MDD). Although there is evidence that neuromodulation induces changes in neurotrophic factors in brain regions implicated in MDD, and that peripheral gene expression is a useful surrogate for CNS activity in humans, there has been no investigation of the peripheral gene expression changes induced by ECT in MDD patients. Working with collaborators at UCLA, Dr. Congdon will leverage peripheral blood samples collected from MDD patients and matched controls enrolled in an ongoing neuroimaging study. She will test a neurotrophic hypothesis of MDD by identifying gene expression correlates of ECT response and risk of relapse in this sample of patients, and by integrating gene expression biomarkers with neuroimaging biomarkers. This research has the potential to delineate changes in gene regulation that underlie treatment response and risk of relapse in MDD.

Project title: Understanding the Relationship Between Adolescent Identity and Substance Use

Mentors:

Paul Chung, MD, MS – UCLA
Mitchell Wong, MD, PhD – UCLA
Gery Ryan, PhD – RAND
Chi-Hong Tseng, PhD – UCLA

Multidisciplinary Expertise:
General Pediatrics, School Health, Substance Use Prevention, Health Services Research

Project Description:
This project examines how self-concept, a potentially modifiable predictor of substance use, might be harnessed to prevent adolescent substance use. Using a mixed methods approach, we will first identify individual, family, peer and school-level predictors of healthy self-concept using cross-sectional survey data from 933 at-risk adolescents. In phase II, we will conduct semi-structured interviews with 40 high-risk adolescents to understand how different aspects of self-concept relate to substance use. We will use these findings to develop additional identity-related measures specific to risky health behaviors and examine their utility with current self-concept scales. In phase III, we make use of the first 3 waves of a longitudinal survey following 960 low-income adolescents from the end of 8th grade through the end of 10th grade to determine whether exposure to highly supportive schools impacts self-concept and whether changes in self-concept predict changes in substance use over time.

Project title: Role of IL-1β and the NLRP3 Inflammasome in the Development of Hypoxemia in Acute Lung Injury

Mentors:

Moshe Arditi, MD – Cedars-Sinai Medical Center
Paul Noble, MD – Cedars-Sinai Medical Center

Multidisciplinary Expertise:
Pulmonology, Critical Care, Immunology

Project Description:
Acute Respiratory Distress Syndrome (ARDS) is a clinical syndrome of acute lung injury and failure characterized by a sudden onset and a profound inability of the lungs to oxygenate the blood (hypoxemia). ARDS has a mortality rate of 30% and is responsible for 75,000 deaths annually in the United States. Despite several decades of research, we still do not understand why ARDS develops and no treatments have been found. Interleukin 1β (IL-1B) is a potent pro-inflammatory cytokine that is implicated in the pathogenesis of ARDS; its secretion is regulated an intracellular complex termed the NLRP3 inflammasome. Our preliminary data in a mouse model suggests a novel role for the NLRP3 inflammasome and IL-1B specifically in the severe hypoxemia seen in ARDS. The purpose of this investigation is to elucidate the mechanism for IL-1B?dependent hypoxemia in ARDS.

Project title: Relationship of physical activity to hippocampal structure and memory in MCI

Mentors:

Gary Small, MD, MS – UCLA
Susan Bookheimer, MD, PhD – UCLA
Bruce Dobkin, MD – UCLA

Multidisciplinary Expertise:
Geriatric psychiatry, dementia, neuroscience, neuroimaging

Project Description:
This observational study aims to examine the effects of physical activity levels on hippocampal structure and memory in older adults with mild cognitive impairment (MCI). Volunteers will have their physical activity monitored for two weeks at a time over a year and a half. Dr. Merrill will test memory and measure hippocampal structure at the beginning of the study and again 18-months later using neuropsychological testing and high resolution magnetic resonance imaging (MRI) to understand the relationship of these factors to physical activity levels in MCI volunteers. Dr. Merrill will also measure potentially related factors such as vascular health, family history of dementia, APO-E genotypes, etc., both to control for these potential confounds and to examine any interactive effects of these variables. This paradigm will establish a methodology within which to then test lifestyle interventions in populations at risk of developing Alzheimer’s disease and related dementias.

Michael Shino, MD, MSCR
Clinical Instructor
Division of Pulmonary and Critical Care Medicine
UCLA

Project title: Mechanisms of allograft injury and the development of bronchiolitis obliterans syndrome after lung transplantation

Mentors:

John Belperio, MD - UCLA
Robert Elashoff, PhD – UCLA
Elaine Reed, PhD - UCLA

Multidisciplinary Expertise:
Lung transplantation, acute lung injury, immunology, immune monitoring, chemokine analysis

Project Description:
Chronic rejection or bronchiolitis obliterans syndrome (BOS) is the major factor limiting long-term survival after lung transplantation (LT). The pathogenesis of BOS remains unknown with no effective treatments. Thus, the identification and avoidance of BOS risk factors is critical.  Prior studies of BOS have traditionally focused on the effects of individual “insults” (e.g., infection, acute rejection, ischemia-reperfusion,  gastroesophageal reflux) to the allograft. In contrast, this project will investigate the association between allograft "injury" and the development of BOS. Our preliminary data suggests that the histopathologic patterns of allograft injury are much stronger determinants of BOS development than the various insults causing them. Furthermore, we find that this association may be mediated by an aberrant Type I immune response involving CXCR3/ligands. Gaining a better understanding of the risk factors and mechanisms responsible for BOS development will lead to novel ways to predict, prevent and treat this devastating syndrome.

Project title: Minimizing Errors in Medication Histories Obtained at Hospital Admission

Mentors:

Douglas Bell, MD, PhD – UCLA
Cynthia Jackevicius, PharmD, MSc – VA Greater Los Angeles Healthcare System
Andre Rogatko, PhD – Cedars-Sinai Medical Center
Rita Shane, MD – Cedars-Sinai Medical Center

Multidisciplinary Expertise:
Health services research, clinical informatics, hospital medicine, clinical trials, medication management

Project Description:
Dr. Pevnick will study three interventions to improve the accuracy of medication histories obtained at hospital admission. The interventions will target elderly and chronically ill patients prone to erroneous medication histories and resultant medication errors. For targeted patients, Dr. Pevnick will test the effect of using pharmacists and pharmacy technicians to obtain an initial medication history. He will also study the potential benefit of accessing electronic claims data at the time of admission to improve medication history accuracy. This project holds promise for understanding how best to apply three promising, emerging interventions to improve medication history accuracy. Improving the accuracy of admission medication histories is accepted as a necessary first step in preventing adverse drug events, which cause over 100,000 deaths in hospitalized patients annually. Beyond studying potential solutions to this public health threat, the proposed research will help to develop Dr. Pevnick into an independent investigator.

Project title: Single Fraction vs. Multiple Fraction Radiation for Patients with Advanced Cancer and Painful Bone Metastases

Mentors:

Neil Wenger, MD, MPH – UCLA
Michael Ong, MD, PhD – UCLA
Michael Steinberg, MD – UCLA

Multidisciplinary Expertise:
Palliative Care, Radiation Oncology, Ethics, Health Services Research

Project Description:
One example of a quality gap that has been identified by recent studies of supportive cancer care quality is the high rate of multiple fraction (compared to single fraction) palliative radiation for patients with advanced cancer and painful bone metastasis despite evidence suggesting that there are similar pain outcomes and that the burden of multiple treatments may impact quality of life negatively. The goal of this career development award is to use quantitative and qualitative methods to evaluate current practice and develop an intervention to improve radiation oncology practice that translates the best evidence from clinical trials into practice. A successful intervention aims to improve quality of life and satisfaction for a particularly vulnerable patient population while potentially decreasing healthcare costs.

Project title: Sensitization of castration-resistant prostate tumors to docetaxel treatment by green tea and quercetin

Mentors:

Jaydutt Vadgama, PhD – Charles R. Drew University of Medicine and Science
Susanne Henning, PhD, RD – UCLA
David Heber, MD, PhD – UCLA

Multidisciplinary Expertise:
Translational nutrition and cancer research, Oncology, Toxicology, Biostatistics

Project Description:
Chemotherapy with docetaxel (Doc), a cell division inhibitor, is a standard treatment for metastatic and castration-resistant prostate cancer (CRPC). However, acquired resistance to Doc develops early in most patients. My project is designed to elucidate the molecular mechanisms of Doc resistance and to determine whether natural products green tea (GT) and quercetin (Q) will reverse the chemoresistance and enhance the efficacy of Doc. Both GT and Q selectively inhibit cell proliferation, induce cell cycle arrest and apoptosis in prostate cancer cells without affecting normal cells. Combined treatment with GT and Q enhanced the antiproliferative effect of Doc 5-fold in cultured castration-resistant prostate cancer cells, associated with increased apoptosis, cell cycle arrest and decreased multidrug resistance protein expression. The proposed mouse study will test the combined effect in vivo. This project will set the stage for future clinical trials to enhance drug efficacy at lower doses and reduce side effects.

Lundquist/Harbor-UCLA

Project title: Using Research in Vancomycin-Resistant Enterococcus to Validate an Efficient System of Quantifying Antibiotic Utilization

Mentors:

Loren G. Miller, MD, MPH – Lundquist/Harbor-UCLA

Susan S. Huang, MD, MPH – UC Irvine

Martin F. Shapiro, MD, PhD – UCLA

Multidisciplinary Expertise:
Infectious Disease, Health Services Research, Clinical Trials, and Clinical Outcomes Research

Project Description:
Approximately 100,000 Americans die every year from infections acquired in hospitals. HAI due to Vancomycin-resistant Enterococcus spp. (VRE) are of particular concern. VRE HAI’s disproportionately affect the most immunocompromised hosts, such as organ transplant recipients, and the severely immunosuppressed. Each VRE bloodstream infection (VRE-BSI) is associated with $50,000 of additional healthcare costs and a 35% attributable mortality. The purpose of this investigation is to 1) evaluate the association between antibiotic use and VRE-BSI incidence, 2) investigate VRE-BSI outcomes using improved methodologies, and 3) validate an electronic source of patient-level antibiotic usage data that can be used for investigations of VRE-BSI and further research on other important pathogens.

Dr. McKinnell will work to develop a database to evaluate the association between antibiotic use, VRE-BSI incidence, and outcomes of patients with VRE-BSI from data derived from Ronald Reagan Medical Center. He will also lead efforts to conduct a retrospective chart review to define the predictors of treatment success among hospitalized patients with VRE-BSI and validate the antibiotic database.

Mary E. Sehl, MD, PhD

Assistant Clinical Professor of Medicine

Division of Hematology-Oncology, UCLA

Project title: Modeling of EMT/MET transitions in breast cancer stem cells

Mentors:

Kenneth Lange, Ph.D. - UCLA

Gay Crooks, M.B.B.S. - UCLA

Max Wicha, M.D. – University of Michigan

Multidisciplinary Expertise:
biomathematics, oncology, cancer stem cells

Project description:
Breast cancer is the most common type of cancer diagnosis in women, with the majority of deaths caused by distant recurrence.

Stem cell-targeted therapies offer new hope in eradicating breast cancer stem-like cells that lead to recurrence after standard therapies fail. Mathematical models have proven useful in studying the population dynamics of cancer stem cells under targeted therapy and are informative in assessing safety and duration of therapy. However, the complexities of the stem cell microenvironment limit the predictive ability of analytic models and suggest the necessity of more informed modeling strategies.

Stochastic simulation methods model rare events that are important in cancer modeling, such as extinction and mutation, and have the ability to address complex dynamics and incorporate feedback of reaction networks in systems biology.  We postulate a model in which breast cancer stem-like cells freely convert between an epithelial (proliferative) and mesenchymal (quiescent, invasive) state, through epithelial-to-mesenchymal transition (EMT) and the reverse process (MET). The mesenchymal state is identified by CD44, a marker of cell adhesion and invasive potential, while epithelial stem cells can be CD44 negative and express ALDH, a marker of mammary stem cells and predictor of poor clinical outcome (6). Cytokines such as IL-6 and TGF-beta, as well as intracellular signaling and miRNAs, may regulate the interconversion of breast cancer stem-like cells between EMT-like and MET-like states. 

We propose a combination of theoretical modeling with experimental validation to study the rates and regulators of EMT/MET transitions in breast cancer stem-like cells. We apply our model to predict alterations in stem cell populations and their regulatory pathways in response to niche-targeted therapy. Ultimately, predictions of therapeutic efficacy and safety could be validated in clinical trials and used to guide drug development and plan therapy duration. We envision that extinction models will provide a novel approach to therapeutic design.

Mentors:

Steven M. Dubinett, MD – UCLA

Hong Wu, MD, PhD – UCLA

Multidisciplinary Expertise:
Translational cancer research, signal transduction, metabolism, lung carcinogenesis, genetically engineered mouse models of lung cancer, micro PET-CT imaging

Project Description:
My project focuses on identifying and testing novel therapies for the treatment of early stage LKB1-deficient lung tumors. The LKB1 tumor suppressor functions as a master regulator of cellular growth, metabolism and survival.  Importantly, the LKB1 gene is frequently mutated in ~35% of non-small cell lung cancer (NSCLC) however, the molecular mechanisms driving tumor growth following LKB1 mutations are poorly understood and to date there are no therapies that target LKB1-deficient lung cancer.  As more targeted therapeutics for NSCLC are needed, I explored use of biguanides, traditionally used to treat diabetes, as metabolic stress agents to target LKB1-deficient lung tumors.  At a cellular level, LKB1-deficient tumor cells are unable to respond to energy stress and selectively undergo increased apoptosis following treatment with metabolic stress agents such as biguanides. The selective sensitivity of LKB1-deficient tumors to metabolic stress presents an Achilles heel to exploit and opens a therapeutic window from which to target LKB1-deficient cells. Additionally, loss of the LKB1 gene results in elevated mTOR signaling that results in increased tumor growth and proliferation.  My project will investigate the use of biguanides (metformin or phenformin) in combination with targeted mTORC1 inhibitors (rapamycin or INK128) for the treatment of LKB1-deficient NSCLC.  I will perform preclinical studies using genetically engineered mouse models of lung cancer to assess the efficacy these novel drug combinations in vivo.  Using micro 18FDG-PET and bioluminescence imaging in combination with detailed immunohistochemical and biochemical analysis I will dissect the molecular signaling pathways driving tumor growth and survival in LKB1-deficient lung tumors. With this multifaceted approach I aim to uncover novel pathways that can be exploited therapeutically in LKB1-deficient tumors. My overarching goal is to identify new, clinically relevant therapeutic strategies to treat patients with NSCLC harboring LKB1 mutations.