2007 K12 Scholars

Jennifer Lee, MD, Assistant Professor, Department of Internal Medicine, Division of Endocrinology, Clinical Nutrition, and Vascular Medicine

Mentors:     Lars Berglund, MD, PhD, Associate Dean of Clinical and Translational Research, Director of the Clinical and Translational Science Center (CTSC); Professor, Department of Internal Medicine, Division of Endocrinology, Clinical Nutrition, and Vascular Medicine

Ellen Gold, PhD, Professor and Chief, Division of Epidemiology, Department of Public Health Sciences

Research Study: Endogenous Sex Hormones, Related Gene Factors, and Risk of Stroke

Abstract:  link

ABSTRACT: Endogenous Sex Hormones, Related Gene Factors, and Risk of Stroke

Introduction:  The incidence of stroke dramatically increases around the menopausal transition in women and in elder men, becoming the 3^rd leading cause of death and a leading cause of morbidity in the U.S.  About 80-85% of all strokes are ischemic.  Estrogen and androgen may affect susceptibility to and outcomes of stroke in both women and women.  In most animal studies, treatment with estrogen limits damage from ischemic stroke.  The few observational studies in women have found no association of endogenous estrogen levels with risk of stroke, but randomized trials of estrogenic agents, including the WHI and the recent LIFT trial of tibolone, have shown that estrogen increases stroke risk in postmenopausal women.  Endogenous testosterone may also influence the risk of stroke partly because conversion of androgens is a major source of estrogen in postmenopausal women.  Testosterone and estrogen also influence inflammation, hemostasis, and lipids during the menopausal transition.  This evidence suggests that genes encoding sex hormone receptors may be candidate genes for stroke susceptibility. 

Aims:  The primary goals are to use a molecular and genetic epidemiologic approach to determine the role of endogenous sex hormones in the risk of stroke and to better identify women and men at high risk so that new hormonal strategies for prevention and treatment can be developed.  The specific aims of the study are:  1) To determine whether the balance of endogenous estrogen and androgen affect intermediate cardiovascular risk factors of inflammation, hemostasis, and lipidemia during the mid-life menopausal transition in women;  2) To determine whether endogenous sex hormones affect the risk of subsequent stroke in older postmenopausal women and age-comparable men and, if an association is found, to test whether the association differs by gender or ethnicity; and 3) To determine whether polymorphisms in the genes encoding for sex hormone receptors affects the risk of subsequent stroke in older postmenopausal women and age-comparable men, and if an association is found, to assess preliminarily whether the effect of hormone levels on stroke risk are mediated by such genetic variants.

Methods:  For Aim 1, cross-sectional and longitudinal study analyses will be conducted in recently menopausal women of different ethnic/racial backgrounds.  For Aims 2 and 3, a nested case-control study of incident strokes will be performed elder Black and White men and women.  A multidisciplinary team of mentors and advisors will provide training and education in the relations between sex hormones and lipid metabolism, reproductive epidemiology, estrogen therapies in cardiovascular disease in women, statistical genetics, stroke neurology, and animal models of sex hormones in stroke.  They will also share research resources, including those at the Clinical Translational Science Center.

Strengths:  1) The proposed studies are efficient, multi-disciplinary, and could have a major translational impact on understanding the gender and racial differences in stroke pathogenesis and on women’s health.  2) The study applies state-of-the-art tools of molecular epidemiology to rigorous phenotyping of large populations.  3) Findings could lead to clinical tests to stratify the risk of stroke and guide use of estrogen-modulating therapies, such as selective estrogen receptor modulators (SERMs) and aromatase inhibitors for stroke prevention.  4) This work would provide a template for future studies of endocrine causes and preventive treatment of other complex diseases.

Michael Minzenberg, MD, Assistant Professor, Department of Psychiatry and Behavioral Sciences

Mentors:   Cameron Carter, MD, Professor, Department of Psychiatry and Behavioral Sciences

                 Charan Ranganath,PhD, Associate Professor, Department of Psychology

Research Study:  Use of fMRI to Study the Mechanism of Action of a Novel Treatment for Memory Dysfunction in Schizophrenia

Abstract:  link

ABSTRACT:  Use of fMRI to Study the Mechanism of Action of a Novel Treatment for Memory Dysfunction in Schizophrenia

Schizophrenia is a chronic serious mental illness with a high domestic and global public health impact. It is characterized by significant cognitive dysfunction, which is observed at the outset of illness, predating medication exposure, is persistent during periods of remission from symptoms, and strongly related to functional outcome. Memory impairments are among those cognitive deficits which are most severe and most predictive of outcome. This includes both working memory and longterm memory, both of which are strongly dependent on the prefrontal cortex (PFC). In addition, the existing antipsychotic pharmacopoeia confers modest benefit at best for memory impairment. Therefore, advances in the identification and evaluation of novel medications for cognitive dysfunction hold the potential to alleviate a significant global disease burden. This progress will require the study of pharmacological effects on cognition with a sophisticated methodology to evaluate the functional neuroanatomy of cognition. Functional magnetic resonance imaging (fMRI) offers this potential by combining good spatial and temporal resolution of neural activity during cognitive tasks, and safely and easily accommodates repeated testing of patients. The present application proposes to use fMRI to test the neural effects of a novel medication for remediation of memory impairment in schizophrenia. Modafinil is an FDA-approved medication which causes elevations in neurotransmitters in the cortex such as dopamine, norepinephrine and glutamate, which are all involved in the modulation of memory processes. It has been shown to improve memory performance in animal models, healthy adults and individuals with psychiatric disorders, including schizophrenia. It is also well-tolerated, with a low incidence of adverse effects compared to antipsychotic medications, and a low abuse potential compared to psychostimulants.   We will first employ a double-blind, placebo-controlled crossover study design to test the effects of a single-dose of modafinil (added to existing patient medication regimens) on PFC neural activity measured by fMRI during a working memory task, in both healthy adults and adults with schizophrenia. We predict that the patients will show impaired PFC activity during working memory function, and impaired subsequent longterm memory performance, and that modafinil will be associated with improved PFC activity during working memory function, which will be associated with improvements in subsequent longterm memory performance. We will then test the effects of a more sustained treatment course of modafinil on these measures in the same group of schizophrenia patients. Following the single-dose treatment phase, all patients will be randomized to a 4-week course of either modafinil (at the same daily dose as the single-dose phase) or placebo. We predict that a 4-week course of modafinil will be associated with greater PFC activity during working memory, and greater subsequent longterm memory performance, compared to both the 4-week placebo-treated group and to the effects of a single dose of modafinil.

Chong-xian Pan, MD, PhD, Assistant Professor, Department of Internal Medicine, Division of Hematology/Oncology

Mentors:        Kit S. Lam, MD, PhD., Professor and Chief, Division of Hematology/Oncology

Ralph de Vere White, MD, Professor, Department of Urology, and Director, UC Davis Cancer Center

Research Study: Targeting Bladder Cancer with Cancer-specific Ligands

Abstract:  link

ABSTRACT: Targeting Bladder Cancer with Cancer-specific Ligands

Background:    Bladder cancer is the fourth most common cancer in male and ninth in female in the United States. Most bladder cancer patients (75%) present with superficial diseases that can be easily accessible for targeted therapy through intravesical instillation. Bladder is relatively isolated from the rest of the human body and has only a few types of confounding cells. The long-term goal of this project is to develop cancer-specific ligands using combinatorial chemistry approaches.

Preliminary Data:        Bladder cancer and normal urothelial cells have different cell surface molecules. I have screened high throughput combinatorial peptide libraries such as one-bead one-compound (OBOC) peptide libraries against bladder cancer, normal urothelial and blood cells to identify the ligands that specifically target molecules on bladder cancer cells. So far, I have identified several peptides that can specifically bind to bladder cancer cells but not the confounding cells such as normal urothelial or blood cells in urine. In this project, I will optimize the binding affinity of these ligands with the OBOC technology, and determine the preclinical and clinical applications.

Hypothesis:

1. Bladder cancer cells have distinct cell surface molecules that can be targeted for diagnosis, imaging and targeted therapy
2. Cancer-specific ligands can be identified by screening high throughput combinatorial chemistry libraries such as OBOC.
3. The binding affinity of cancer-specific ligands will be further improved with optimization.

Specific Aims:

Aim 1. To identify and optimize ligands specifically targeting bladder cancer cells. 

Aim 2. To determine (1) the in vivo targeting capacity of the cancer-specific ligands using an orthotopic superficial bladder cancer mouse model that mimics superficial bladder cancer in patients; (2) the in vivo targeting capacity and biodistribution of the cancer-specific ligands with subcutaneous bladder cancer model that mimics distant metastasis in patients.

Aim 3. To determine (1) if the bladder cancer-specific ligands can capture and enrich bladder cancer cells in urine samples for diagnosis; (2) if the bladder cancer-specific ligands can target bladder cancer in specimens from patients.

Significance: The bladder cancer-specific ligands developed in this project have the potential to capture cancer cells in urine for diagnosis and follow-ups, targeted therapy through intravesical instillation for superficial cancer, imaging detection of superficial and metastatic bladder cancer and targeted therapy for metastatic bladder cancer.

Ulfat Shaikh, MD, MPH, Assistant Professor, Department of Pediatrics

Mentors:   Patrick S. Romano, MD, MPH, Professor of Medicine & Pediatrics

Thomas S. Nesbitt, MD, MPH, Professor of Family & Community Medicine

Dennis M. Styne, MD, Professor of Pediatrics & Division Director, Pediatric Endocrinology

Research Study: Enhancing Pediatric Obesity Prevention in Rural Clinics

Abstract:  link

ABSTRACT:  Enhancing Pediatric Obesity Prevention in Rural Clinics

Rural populations face disparities with respect to health status, healthcare services, and medical research. Preliminary data suggest that obesity is more prevalent in rural than in urban counties in California. Although healthcare provider screening for obesity is associated with increased weight management counseling and patient risk factor reduction, healthcare providers infrequently screen children. Little is known about how to improve provider screening and counseling, particularly in disadvantaged rural areas. The proposed research plan will test the effect of a theoretically grounded and integrated intervention delivered through telehealth (clinical telemedicine, distance education, and internet communication), on screening and counseling for pediatric obesity prevention in rural clinics. Eligible rural clinics and their providers will be randomized to receive the integrated intervention or usual methods for provider education.  Such rigorous and hypothesis-driven research is required to improve healthcare quality for pediatric obesity prevention in rural areas.