2015 CTRI Pilot Project Recipients

Clinical Research | Translational Research | Innovative Technology | Personalized Medicine | Academic-Community

The CTRI announces the selection of the 2015 Pilot Projects. Fifteen projects were chosen in five categories, including Clinical Research, Translational Research, Innovative Technology, Personalized Medicine, and Academic-Community Partnership. Pilot Project grants are one-year competitive cash awards for researchers to obtain preliminary data. Funding priority is given to junior faculty members. Below are the 2015 projects.

Funding Period is 8/13/2015 through 3/31/2016.

Clinical Research Pilot Projects

Seema Aceves, MD, PhD Seema Aceves, MD, PhD
UC San Diego Department of Pediatrics
Department contributed to pilot project funding

Title: The Role of LIGHT in Esophageal Remodeling in Pediatric Eosinophilic Esophagitis

Tissue remodeling is the mechanism for clinical complications in a number of chronic immunologic diseases. Fibrosis is responsible for significant end organ dysfunction but most existing therapeutics offer variable fibrotic control. Biopharmaceutical and clinical communities perceive the treatment of tissue remodeling as a primary unmet need. Understanding factors that initiate and/or maintain fibrosis will elucidate novel therapeutic targets. Eosinophilic esophagitis (EoE) is a chronic, antigen-driven Th2 eosinophilic disease. Esophageal remodeling causes tissue rigidity, strictures, dysphagia, and food impactions. EoE requires repeated tissue analysis and has limited therapeutic options. The Croft laboratory discovered that LIGHT (TNFSF14) is pivotal to lung and skin fibrosis in murine models. Dr. Aceves was the first to define the mechanisms of remodeling in pediatric EoE. We aim to understand LIGHT and LIGHT receptor expression in EoE based on novel findings supporting a possible role for LIGHT. The long term goal is to understand LIGHT action in the esophagus using preclinical models and, since essentially nothing is known about LIGHT in human disease, our studies could lead to impactful, translational results. The novelty of the proposed studies is the identification of LIGHT, a ligand that promotes primary features of tissue remodeling and fibrosis including extracellular matrix protein deposition and up-regulation of remodeling factors including TGFb1 in EoE.

We have more than 700 pediatric EoE subjects and access to fresh and archived esophageal biopsy samples. Since EoE biopsies show cardinal features of remodeling including fibrosis, epithelial hyperplasia, and expression of TGFb1, an assessment of LIGHT and its receptors in clinical samples with varying severities of EoE represents a strong translational study that could spearhead multiple in-depth analyses.

Mick Croft, PhD, from the La Jolla Institute for Allergy and Immunology will provide input on the project.

Joshua Alexander, DO, MPH Joshua Alexander, DO, MPH
UC San Diego Department of Neurosciences
Department contributed to pilot project funding

Title: The Role of Osteopathic Medicine in the Management of Post-traumatic Migraine

Headache is an important and very common somatic complaint among people with traumatic brain injury and an important cause of disability in the United States. The most common type of headache reported is migraine without aura. Hoffman and colleagues noted that 41 percent of participants in their study had post-traumatic headache despite treatment with lifestyle modifications and pharmacotherapy. The role of osteopathic manipulation (OM) in the management of post-traumatic headaches has not been extensively explored. A case report from 2009 suggests that OM may have a role in the management of chronic post-traumatic headache. Studies support its use for non-traumatic migraine. However, there are no pilot or large-scale studies evaluating the role of OM in the management of post-traumatic migraine.

We will evaluate the use of osteopathic manipulation as a treatment to reduce headache symptoms and decrease disability as measured by the reliable and valid MIDAS. This is a 36-week prospective study in which 20 participants from the community will be randomized into a standard of care arm and a standard of care plus osteopathic manipulation arm.

The study will involve the Departments of Neurosciences and Family and Preventive Medicine.

Joel Baumgartner, MD Joel Baumgartner, MD
UC San Diego Department of Surgery
Department contributed to pilot project funding


Title: Pilot Study of Postoperative Chemotherapy in High-Grade Appendiceal Adenocarcinoma with Peritoneal Carcinomatosis

Appendiceal cancers are rare tumors, with an annual incidence of five/million in the US; but they are a significant cause of morbidity and mortality as one-third of affected patients develop peritoneal metastases. Patients with high-grade subtypes of appendiceal carcinoma with peritoneal metastases have a poor prognosis, with a five-year survival rate of less than 50 percent. Surgical resection (cytoreductive surgery – CRS) in combination with regional chemotherapy, in the form of hyperthermic intraperitoneal chemotherapy (HIPEC), is a valuable treatment option for patients with limited peritoneal metastases from high-grade appendiceal carcinoma. However, this treatment often fails to achieve long-term disease control with relapses typically occurring within 7-12 months. 5-fluorouracil (5-FU)-based systemic chemotherapy has a response rate of 25-44 percent in this disease. High expression of vascular endothelial growth factor receptor 2 (VEGFR-2) is common in this disease and treatment with the anti-VEGF antibiody bevacizumab has a 44 percent response rate in combination with 5-FU-based chemotherapy. Combinations of systemic chemotherapy with CRS/HIPEC may improve outcomes, but postoperative chemotherapy is not standardized and there are no prospective studies in this setting. We hypothesize that a standardized low-toxicity chemotherapy regimen (5-FU/bevacizumab) may improve progression-free survival (PFS) in patients with high-grade appendiceal peritoneal carcinomatosis following CRS/HIPEC.

This is a single-arm, prospective, pilot study of systemic chemotherapy (5-FU/bevacizumab) after CRS/HIPEC. The primary objective will be to determine if postoperative chemotherapy improves PFS in patients with peritoneal carcinomatosis secondary to high-grade appendiceal carcinoma after CRS/HIPEC versus historic controls at our institution. Secondary objectives will be to determine if postoperative chemotherapy improves overall survival, is safe and improves quality of life in this population.

Tiffany Greenwood, PhD Tiffany Greenwood, PhD
UC San Diego Department of Psychiatry
Department contributed to pilot project funding

Title: Are Bipolar Brains Creative Brains? Investigation of Regional Activation and Neural Connectivity in Bipolar Patients and Artists Towards a Model of Creativity as a Positive and Evolutionarily Adaptive Trait within the Bipolar Spectrum

Bipolar disorder (BD) is a severe, lifelong illness for which lasting remissions are uncommon. Understanding the underlying pathophysiology and genetic architecture is of paramount importance to diagnosis and treatment. Recent studies suggest that common variation explains >25 percent of the genetic variance in BD, 68 percent of which is shared with schizophrenia as a general risk for psychosis, although the risk mechanism remains unknown. Despite considerable fitness costs, BD has persisted in the population with a high heritability and stable prevalence, contrary to a simple purifying selection model of evolution. We alternatively propose that BD is maintained in part through balancing selection, whereby risk variants in mild or moderate doses confer adaptive advantages as positive traits that increase fitness in allele carriers, which serve to offset the deleterious effects of illness on fitness. The balancing selection model is consistent with the observation of certain positive traits or enhanced abilities within the BD spectrum and in unaffected relatives. It is also consistent with the inverted-U relationship between psychosis and creativity and a shared vulnerability, where creativity and other positive traits presumably increase with genetic loading for BD up to a threshold, beyond which they start to diminish with the increasing impairment. This model also suggests the influence of common variants distributed across the entire population, consistent with both polygenic models of BD risk and the observance of a stable worldwide prevalence. Clinically unaffected individuals thus serve as the genetic reservoir for these positive, adaptive traits and benefit from the increased fitness they confer.

Here we propose to use functional magnetic resonance imaging to explore individual differences in brain activity and connectivity in 12 each of BD patients, creative controls, and non-creative controls matched for age, gender, education, and ethnicity. The project is designed to help identify brain regions potentially involved in creative processes; determine whether baseline connectivity and activation of these regions differs in BD compared to controls; assess the relevance of positive traits, including demonstrated creative abilities; and evaluate clinical, demographic, and genetic factors. Since many BD patients consider increased creativity a positive aspect of their illness and often discontinue their medications due to experiences of diminished creativity, studying the link between creativity and BD is critical to promoting a deeper understanding of patients' needs and facilitating better, more individualized treatment.

Monica Guma, MD, PhD Monica Guma, MD, PhD
UC San Diego Department of Medicine
Department contributed to pilot project funding

Title: Eicosanoids as Biomarkers of Psoriatic Arthritis

Psoriatic arthritis (PsA) is an inflammatory arthritis affecting the joints and connective tissue and is associated with psoriasis of the skin or nails. PsA is a progressive disorder ranging from mild synovitis to severe progressive erosive arthropathy, which progresses over time. Early diagnosis and aggressive treatment are key if the damage caused by this disease is to be controlled. Biomarkers useful in diagnosis of patients with psoriasis at risk of developing PsA remain an unmet medical need as current biomarkers do not differentiate between inflammation coming from different sources such as skin or synovium.

Lipidomics is a lipid-targeted metabolomics approach aimed at comprehensive analysis of lipids in biological systems. It has become clear that many of the signaling pathways triggered by inflammatory cytokines that are activated during inflammation have a profound effect on core lipid metabolism of cells and the study of the lipidome has been successful in identifying prognostic biomarkers. Eicosanoids, including prostaglandins and leukotrienes, are biological lipids that have been implicated in various pathological processes such as inflammatory arthritis and skin diseases.

We have recently obtained preliminary data in blood samples of PsA patients, in which a different eicosanoid profile was associated with either parameters related to joint inflammation or skin involvement, suggesting that eicosanoid profile in blood could potentially differentiate between inflammation coming from different sources, such as skin or joints. By defining more precisely eicosanoid profiles in the plasma of patients with skin psoriasis or PsA, we may identify biomarkers that will help in the diagnosis of patients with psoriasis at risk of developing PsA. Thus, we will test the hypothesis that the eicosanoid profile would differentiate between sources of inflammation such as joints or skin.

The first aim is to analyze a complete eicosanoid panel in skin biopsies and serum of psoriasis patients. The second is to analyze the eicosanoid profile in the serum of PsA patients with active synovitis, with or without active skin psoriasis. All patients will get clinical joint activity and skin scores. The results will help determine whether the eicosanoid profile in plasma is different in patients with only skin disease, joint disease or both, and if the different eicosanoid signatures detected in blood correlates with skin and synovitis scores.

Taraneh Paravar, MD, from the UC San Diego Department of Dermatology will be involved in the project.

Sanjay Mehta, MD Sanjay Mehta, MD
UC San Diego School of Medicine
Department contributed to pilot project funding

Title: Optimizing Vaccine Efficacy in Solid Organ Transplant Recipients

Solid organ transplant recipients require the use of immunosuppressive medications to prevent rejection of the transplanted organ. Unfortunately, these medicines also lead to blunting of the immune response, which predispose these subjects to infectious complications. Vaccination can be used to protect transplant recipients against particular pathogens. However, immunosuppressive medications may also blunt vaccination responses, thus rendering them less effective in this population. Previous work has demonstrated that the response to a vaccine is dependent upon the vaccination schedule, the timing in relation to other vaccinations, adjuvants, and the vaccine antigens themselves. Moreover, the persistence of a vaccine response is dependent upon the induction of a CD4+ T cell response and eventual persistence of memory B cells. Antigen presenting cells pick up vaccine antigens and adjuvants to skew the immune response. To generate neutralizing antibodies, a subset of CD4+ T cells called T follicular helper cells orchestrate the B cell response, allowing for survival of antigen specific memory B cells. These antigen specific memory B cells will produce antibodies necessary to neutralize an infection. However, chronic diseases and immunosuppressive medications can theoretically affect antigen presentation, helper T cell responses, and memory B cell persistence.

Objective knowledge about vaccine responses in transplant recipients remains limited. We propose to evaluate the vaccine response in individuals with organ failure both in the pre-transplant and post-transplant period, using a novel microarray approach. An improved understanding of the response to vaccines will help clinicians to optimize both vaccination and immunosuppression protocols in these complex subjects.

This project will involve a collaboration between Scripps Research Institute researchers Luc Teyton and Ryan McBride, who will perform the vaccine antibody response measurements; La Jolla Institute for Allergy and Immunology researchers Jennifer Dan and Shane Crotty, who will perform the analysis of T-cell responses; and UC San Diego researchers Sanjay Mehta and Dianne McKay, who will recruit patients and coordinate the study.

Hilary Roeder, MD Hilary Roeder, MD
UC San Diego Department of Reproductive Medicine

Title: Evaluation of Placenta Growth Factor as a Diagnostic Marker for Late Preterm Preeclampsia

Preeclampsia (PET) complicates 2 to 8 percent of pregnancies and is characterized by placental ischemia and maternal vascular dysfunction. The diagnosis relies on nonspecific clinical criteria including hypertension, proteinuria, or end-organ injury. The evaluation of suspected PET is costly and time consuming, and there is a widely-recognized need for improved diagnostic techniques. Placenta Growth Factor (PlGF) is a promising diagnostic biomarker of PET, as recent evidence suggests it plays an integral role in pathogenesis, especially in preterm cases with placental insufficiency. 

Commercially-available PlGF assays have been introduced for predicting and diagnosing PET. In women with suspected preterm PET, PlGF had a sensitivity of 96 percent and a NPV of 98 percent for a diagnosis of PET requiring delivery. A randomized controlled trial is needed to demonstrate improved pregnancy outcomes and costs when a PlGF-based algorithm is used in managing suspected PET. Prior to this, however, investigators must determine if a PlGF-based diagnosis of PET ("PlGF Triage") is any more accurate or cost-effective than the traditional clinical methods of triage ("Clinical Triage"), which often requires serial observations and laboratory studies. 

The aims of the project are to compare PPV/NPV/sensitivity/specificity of PlGF Triage to Clinical Triage for the prediction of a final, adjudicated diagnosis of PET; compare or describe the spectrum of costs associated with the PlGF Triage and Clinical Triage; and compare the PPV/NPV/sensitivity/specificity of PlGF Trige to ClinicalTriage for the prediction of composite adverse maternal and neonatal outcomes.

Translational Research Pilot Projects

Jeremiah Momper, PharmD, PhD Paula Desplats, PhD
UC San Diego Department of Neurosciences
Department contributed to pilot project funding



Title: The Impact of Circadian Alterations on Brain Insulin Resistance and Alzheimer Disease Pathology

Alzheimer disease (AD) is a multifactorial neurodegenerative disorder that affects more than 5 million Americans over the age of 60. AD is the most common form of dementia manifested clinically by a progressive loss of cognitive function and the pathological accumulation of amyloid-β (Aβ) in amyloid plaques and phosphorylated Tau protein in tangles in the neocortex and the hippocampus. Disruptions in circadian regulation are a prominent feature of neurodegenerative disorders and a major factor of hospitalization and morbidity in AD. Circadian oscillations coordinate physiology with environmental cues and alterations in rhythmicity result in disease, including cognitive decline, diabetes and neurodegeneration.

In mammals, circadian rhythms are generated by the transcriptional oscillation of core clock genes, involving positive regulators BMAL1 and CLOCK and negative regulators CRY and PER. This circadian machinery is present in most cells, including neurons and glia, and regulates the timely expression of hundreds of genes. We have found that circadian cycles are altered in AD patient-derived fibroblasts and that BMAL1 expression is arrhythmic in the frontal cortex of mild cognitive impaired (MCI) and AD cases.

Insulin has a key role in learning and memory and directly regulates ERK, a kinase required for the type of learning and memory compromised in AD. Not surprisingly, insulin resistance has been identified as a major risk factor for the onset of AD. Insulin resistance is associated with a decrease in glucose uptake by neurons; an increase on Aβ production and secretion; the formation of senile plaques and tau phosphorylation.

Insulin degrading enzyme (IDE) is a metalloprotease involved in the degradation of amyloidogenic substrates, including insulin and Aβ. Importantly, emerging evidence supports the notion that circadian disruption leads to insulin resistance associated with altered levels of Bmal1 in mice. Moreover, loss of Period2 increases plasma insulin levels and impairs circadian oscillation of hepatic IDE in mice. However, the relation between alterations on circadian regulation and insulin resistance in the brain is still not fully elucidated, although it might have a major impact on worsening neuropathology and cognitive decline in AD.

Our hypothesis is that alterations in BMAL1 transcription associated with AD and MCI will affect the circadian expression of IDE, triggering brain insulin resistance and aggravating neurodegeneration.

This study will investigate a) the role of BMAL1 on IDE regulation: by manipulating the levels of BMAL1 on neuronal cultures and evaluating its impact on IDE transcription; glucose uptake and insulin receptor phosphorylation; and b) profiling the levels of BMAL1; IDE and phosphorylated-insulin receptor on frontal cortex and hippocampus postmortem samples from healthy age-matched controls, MCI and AD subjects (n=16/group) and analyzing their correlation with number of plaque and tangles; neurodegenerative markers and cognitive scores.

Data analysis will be performed in collaboration with the CTRI Biostatistics Unit.

Jeremiah Momper, PharmD, PhD Jeremiah Momper, PharmD, PhD
UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences
Department contributed to pilot project funding

Title: Regulation of Hepatic UGT1A9 by Sex Hormones: Implications for Mycophenolic Acid Exposure in Renal Transplant Recipients

Kidney transplantation is the treatment of choice for end-stage renal disease. Following transplantation, males experience a 10 percent increased risk of graft loss compared to women (Relative Risk=0.9). These findings are age dependent, and interestingly the differences are more pronounced in patients less than 45 years of age. Mycophenolic acid (MPA), an immunosuppressive antimetabolite drug used in transplant patients, provides a greater reduction in risk for graft loss in women as compared with men (RR 0.53 vs. RR 0.79). MPA is metabolized to a pharmacologically inactive glucuronide metabolite (MPAG) by hepatic UDP glucuronosyl transferases (UGTs), primarily UGT1A9. Preliminary evidence suggests male transplant recipients may have higher glucuronidation of MPA than females. We have previously shown that hepatic UGT1A9 expression is lower in female mice as compared to male mice, and increased in pregnant mice to 70-fold over non-pregnant values. This data suggests that sex hormones play a role in the regulation of UGT1A9. Therefore, patient characteristics including age, menopausal status, and oral contraceptive use could modulate UGT1A9 expression in vivo and subsequently affect exposure to UGT1A9 drug substrates such as MPA. This relationship could have important clinical implications for sex- and age-based differences in drug dosing.

We hypothesize that regulation of hepatic UGT1A9 by sex hormones leads to reduced UGT1A9-mediated MPA glucuronidation in females as compared to males, resulting in sex differences in allograft survival.

The first aim is to characterize sex differences in the hepatic expression and functional activity of UGT1A9 in a humanized mouse model. The kinetic parameters of MPA glucuronidation will be evaluated, including the influence of androgen and estrogen treatments to male mice (+/- castration) and female mice (+/-overectomization). The second aim is to assess the impact of plasma androgen and estrogen concentrations on MPA glucuronidation in adult renal transplant recipients. In this pilot study, the ratio of MPAG/MPA will be evaluated in plasma samples drawn from stable patients for routine immunosuppressive drug monitoring. Modifying factors including age, menopausal status, and oral contraceptive use will be evaluated.

Gerald Morris, MD, PhD Gerald Morris, MD, PhD
UC San Diego Department of Pathology
Department contributed to pilot project funding

Title: Defining Immunologic Effects of Reprogramming Human Tissue Precursors for Regenerative Therapy

The ability to induce pluripotency in human cells has enormous promise for development of regenerative therapies for patients with organ damage from developmental or degenerative disease or trauma. Current efforts focus on in vitro induction of pluripotency in adult cells by expression of critical transcriptional regulators followed by differentiation of these induced pluripotent stem cells (iPSCs) to lineage-committed tissue precursor cells. This approach circumvents use of embryonic stem cells and enables use of autologous cells. However, the immunologic consequences of in vitro cellular reprogramming are unclear, with conflicting data from mouse transplantation models. Defining how in vitro reprogramming affects the immunologic status of tissue progenitor cells is critical to the development of efficacious regenerative therapies.

This project addresses undefined aspects of cellular reprogramming of tissue precursors, including characterization of antigen presenting machinery, aberrant expression of developmentally-restricted proteins acting as neo-self-antigens, and induction of cellular stress responses that may alter immunologic identity.

Collaborating with the laboratory of Louise Laurent, MD, PhD, UC San Diego Department of Reproductive Medicine, we have demonstrated that human iPSCs derived from skin fibroblasts and subsequently differentiated into committed liver and pancreas endoderm precursor cells express antigen processing and presentation proteins, evidenced by gene expression and protein analyses. These results indicate the immunogenic potential of iPSC-derived tissue precursors. The project proposes to identify antigenic peptides presented by iPSC-derived tissue progenitor cells that may stimulate immune responses and begin defining underlying mechanisms. Since immune responses to iPSC-derived tissue precursors are likely to be directed against highly expressed or aberrantly expressed antigens, we propose to define the potential antigenic repertoire of these cells by mass spectrometry analysis (in collaboration with UC San Diego Biomolecular Mass Spectrometry Facility) of HLA-presented peptides. Peptides bound to HLA-A and HLA-DR will be analyzed from lineage-committed hepatocyte precursors derived from skin-fibroblast-derived iPSCs and hepatocytes from organ donors to define potentially immunogenic peptides uniquely present following in vitro reprogramming. The mechanistic basis for generation of neo-self-antigens will be examined by evaluating expression of precursor proteins and antigen processing and presentation machinery. Immunogenicity of these antigens will be assessed by measuring proliferative and effector responses of HLA-matched healthy donor peripheral blood leukocytes following stimulation with peptide antigens of interest. Potential mechanisms for increased immunogenicity resulting from cellular reprogramming will be explored by examining induction of the unfolded protein response and innate immune responses, which have significant cross-talk with antigen processing and presentation pathways. These will be examined using existing gene expression data and by performing Western blot analysis for activation of signaling molecules.

Innovative Technology Pilot Projects

Alysson Muotri, PhD Alysson Muotri, PhD
UC San Diego Department of Pediatrics
Department contributed to pilot project funding

Title: Reverse Transcriptase Inhibitors as a Novel Therapeutical Approach for Neurological Autoimmune Disorders

Accumulation of DNA species in the cytosol leads to a type I interferon response and inflammation. The three-prime repair exonuclease I (TREX1) enzyme removes single-stranded (ss) from the cytosol, preventing accumulation of DNA and a subsequent inflammatory response. Several autoinflammatory/autoimmune diseases, such as Aicardi-Goutières syndrome (AGS) and systemic lupus erythematosus, arise when the function of TREX1 is compromised. AGS is a severe autoinflammatory disorder most typically affecting the brain and the skin, which results in severe psychomotor retardation. Research on the neurological aspects of AGS at a cellular and molecular level has proven difficult due to the lack of relevant animal models. In particular, although demonstrating a lethal inflammatory state, the Trex1 knockout mouse does not exhibit a neurological phenotype, and is thus unsuitable to study AGS neuropathology. Using cutting-edge genome-editing technology, we generated human pluripotent stem cell models devoid of TREX1 function, which we further differentiated into neural cells. Unexpectedly, we found an abundance of ssDNA in TREX1-deficient neurons, and astrocytes. Furthermore, we showed the Long Interspersed Element-1 (L1), a class of endogenous retrotransposons, is the major source of the ssDNA. Next, we treated AGS-derived neurons and astrocytes with reverse transcriptase inhibitor (RTi) HIV drugs Lamivudine (3TC) and Stavudine (D4T), which have been shown to inhibit L1 reverse transcription, and we detected a reduction on ssDNA levels. TREX1-deficient neurons experience greater cytotoxicity, which can be rescued with RTi. Likewise, treating neurons with conditioned media from TREX1-deficient astrocytes increases neuronal toxicity, indicating the presence of toxic factors or lack of neuroprotective elements. Thus, our results demonstrate that TREX1 removes cytosolic ssDNA in neural cells created by L1 reverse transcription, thus preventing neurotoxicity. We propose to further validate the use of RTi as a therapeutical agent for AGS.

To prove the specificity of our RTi drugs, we will treat AGS-derived neurons and astrocytes with Nevirapine, a RTi that does not affect L1 reverse transcriptase. We will measure neuronal toxicity using cleaved caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end-labeling assays.

Reports on AGS patients have highlighted the role of interferon-α (IFNa) as central to disease pathophysiology. We propose to examine IFNa mRNA levels in astrocytes. We will also measure the expression of interferon-stimulated genes that could be upregulated independently of interferon signaling. We will test the efficacy of 3TC and D4T on reducing a potential INFa response in contrast to Nevirapine.

This is the first human model to study the neuropathology of extremely severe autoinflammatory diseases such as AGS. The molecular mechanism proposed is a novel phenomenon and suggests that our own cells can actually accumulate retroviral-like extrachromosomal sequences that trigger an autoinflammatory response in the nervous system. Our data is of high clinical relevance because it suggests that AGS patients could benefit from available FDA and EMEA-approved anti-retroviral drugs. Due to the AGS similarities with lupus erythematosus, our research can be potentially applied to millions of patients affected by these diseases.

Personalized Medicine Pilot Projects

Joseph M. Cantor, PhD Joseph M. Cantor, PhD
UC San Diego Department of Medicine
Department contributed to pilot project funding

Title: CD98hc in Pancreatic Islet Allograft Rejection

Improving pancreatic islet transplantation is an important goal for long-term cure of autoimmune Type I diabetes (T1D). In order to prevent allo- and auto-immune rejection of transplanted islets, patients are typically treated with long-term, broad-spectrum immunosuppression, which has significant side effects, including islet toxicity. Finding better targets for blockade of graft rejection is thus a major priority in achieving immunological tolerance to islet transplants. CD98hc is a new target for blocking rejection of islet allografts by specific interference with clonal expansion of effector T cells. CD98hc is a transmembrane protein that controls effector T cell and B cell clonal expansion. We and others have shown that CD98hc is required for experimental autoimmune diabetes, and more recently that CD98hc deletion allows cardiac allograft acceptance. However, there are critical differences in the immune response to transplanted cardiac vs. pancreatic islet tissue, including the presence of pre-existing autoimmunity in islet transplant recipients. In order to develop future CD98 function-blocking reagents for protection of islet transplants, we will test whether CD98hc is required on T and/or B cells for islet allograft rejection and whether loss of T cell CD98hc results in an increased regulatory T cell response after islet transplant.

Academic-Community Pilot Projects

Amanda Gosman, MD Venessa Malcarne, PhD Amanda Gosman, MD
UC San Diego Department of Surgery


Vanessa Malcarne, PhD
San Diego State University Department of Psychology
Community Partner: Celene A. Nigro, Director of Medical Program, Fresh Start Surgical Gifts

Title: Pediatric Facial Deformity Quality of Life (QoL) Questionnaire Development Study

The study of health-related quality of life (HRQOL) has in recent years become an integral portion of patient-centered outcomes research. It is an ever-growing field and has become critical in the establishment and evaluation of charitable programs and the cost-benefit analysis of medical treatments and interventions. Fresh Start Surgical Gifts (FSSG), a San Diego-based non-governmental organization, has continually sought ways to demonstrate the life-changing effects it has on the patients it serves. This organization has supported our past research studies concerning HRQOL in patients with facial deformities and is now a partner with us in this new study to develop a module of questionnaires to study the HRQOL impact of deformities and their treatments. This tool will be of global importance to the patients we serve both through FSSG and other community and medical groups.

Christina Holub, PhD, MPH Camille Nebeker, EdD, MS Christina Holub, PhD, MPH
San Diego Institute for Behavioral and Community Health; San Diego State University


Camille Nebeker, EdD, MS
UC San Diego Department of Family Medicine and Public Health
Community Partner: Siaosi Veimau, Owner Rawmana Fitness

Title: Increasing Physical Activity through a Culturally Tailored, Community-led Intervention among Pacific Islanders: The Rawmana Fitness Pilot Study

The primary goal of the research study is for Native Hawaiian and Pacific Islander participants of a 12-week culturally-tailored intervention to increase their physical activity level and intensity to meet recommendation guidelines for adults (i.e. 150 minutes of moderate-to-vigorous physical activity per week). The overarching goal is to foster an academic-community relationship with community partner, Rawmana Fitness, and prepare the organization for future full-scale research and collaboration.

The study's primary objective is to determine if Native Hawaiian and Pacific Islander participants in a 12-week culturally-tailored intervention are more likely to meet physical activity guidelines (at least 150 minutes of moderate-to-vigorous physical activity per week) compared to a wait list control group. The secondary objectives are to evaluate body composition (i.e. body fat, weight, and muscle) among Native Hawaiian and Pacific Islander participants in a 12-week culturally-tailored intervention compared to a wait list control group; determine the feasibility and acceptance of traditional research devices that access physical activity (i.e. accelerometers) compared to mainstream wearable devices (i.e. Garmin vivofit); and to improve the capacity and knowledge of the Rawmana Fitness team and the selected community health promoters in research principles and ethics after three research readiness training workshops.