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: 
Introduction:  The incidence of stroke dramatically increases around the menopausal transition in women and in elder men, becoming the 3rd 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: 
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 long-term 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 long-term memory performance, and that modafinil will be associated with improved PFC activity during working memory function, which will be associated with improvements in subsequent long-term 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 long-term memory performance, compared to both the 4-week placebo-treated group and to the effects of a single dose of modafinil.

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: 
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.

Estella Geraghty, MD, MS, MPH, Assistant Professor, Department of Internal Medicine

MENTORS:
Richard Kravitz, MD, MSPH, Professor, Division of General Medicine, Co-Vice Chair (Research), Department of Internal Medicine
Peter Franks, MD, Professor of Family Medicine, Family and Community Medicine
James Case, MS, DVM, PhD, Professor of Clinical Diagnostic Informatics, California Animal Health and Food Safety Laboratory
Anne Kjemtrup, DVM, MPVM, PhD, Research Scientist III, California Department of Public Health, Vector-Borne Disease Section

RESEARCH STUDY:  Aerial Pesticide Spraying for West Nile Virus Mosquito Control and the Incidence of Respiratory Complaints in California, 2005

ABSTRACT: 
Pesticides play an important role in public health as part of a sustainable mosquito control system1. In fact, chemical control with pesticides is still the most important element in the integrated approach to vector management2. The safety of public health pesticide use has long been a concern among international (World Health Organization), national (Centers for Disease Control and Prevention, Environmental Protection Agency), and local agencies (Departments of Public Health). However, since the arrival of West Nile virus (WNV) in the United States, the issue of pesticide safety has also gained sway with the public3, inciting heated debates about the risk-to-benefit ratio for aerial pesticide applications4. This K12 research plan addresses the question of ‘risk’ to human health when pyrethrin pesticides are sprayed aerially for WNV mosquito control, through the use of rigorous and innovative methods.

WNV is a mosquito-borne disease, causing human infections ranging in severity from asymptomatic to fatal. Since there is no specific treatment for WNV, prevention of infected mosquito bites remains the only viable option. So when WNV surveillance established the presence of epidemic conditions in California in 20055, many of the state’s vector control agencies chose adulticiding (killing adult mosquitoes) as the best pest management option to break the WNV transmission cycle and to reduce WNV associated morbidity and mortality6. Pyrethrin-based pesticides were sprayed aerially to cover the large geographic regions showing this epidemic activity. However, the pyrethrin-based pesticides can cause acute human health effects including respiratory problems7, skin and eye irritation, and nervous system disorders8. The potential for aerial pesticide spraying to cause these health effects spurred widespread public fear and led to significant opposition to the spraying program9.

This research focuses on the relationship of aerial pesticide spraying to the incidence of acute physiologic complaints in the California population during the summer of 2005. Previous studies conducted in New York City, showed that ground spraying activities, using pyrethrin pesticides, did not increase emergency room visits for asthma exacerbations7, 10. However, several important questions remain: 1) were environmental variables adequately controlled?, 2) is aerial spraying different than ground spraying?, 3)do aerially sprayed pyrethrin pesticides lead to other acute respiratory conditions in addition to asthma?, and 4) do aerially sprayed pyrethrin pesticides lead to acute neurologic, skin and eye complaints? This proposal will address these questions in the following specific aims.

Specific Aim 1:  Create and validate a prediction model for environmental variables including: five criteria pollutants, pollens, and mold spores by zip code.
Since many pollutants and pollens/mold spores are known to cause respiratory illnesses and exacerbations themselves11-20, this aim addresses the issue of confounding and/or effect modification by developing accurate prediction models for zip code level estimation of these environmental variables. We hypothesize that 1) interpolation techniques for estimating pollutants, and pollens/mold spores are more error prone than prediction models that incorporate additional variables, and that 2) handheld GPS and pollutant monitors can be used as a “gold standard” to test and validate prediction models.

Specific Aim 2:  Examine the incidence of emergency room visits and hospital admissions for all acute respiratory complaints in California, during the summer of 2005, before, during, and after aerial spraying, in areas with and without aerial spraying, adjusting for environmental variables.
We hypothesize that after adjusting for environmental variables, aerial pyrethrin pesticide spraying will not be associated with an increase in the incidence of acute respiratory complaints in sprayed or non-sprayed areas. However, we anticipate that there will be significant variation in acute respiratory complaints (whether in aerially-sprayed areas or not) that are associated with pollutants, pollens and meteorological conditions.

Specific Aim 3:  Examine the incidence of emergency room visits and hospital admissions for acute neurologic, skin and eye complaints in California, during the summer of 2005, before, during, and after aerial spraying, in areas with and without aerial spraying.
Similar to Aim 2, we hypothesize that aerial pyrethrin pesticide spraying will not be associated with an increase in the incidence of acute neurologic, skin or eye complaints in either sprayed or non-sprayed areas.

The rationale for the proposed work is its important public health implications. This study will help to inform public health officials and impact policy as they weigh the risks and benefits of aerial pesticide spraying for WNV vector control. The proposed research is innovative because it applies geographic information systems (GIS) technologies to both the creation of new, validated, prediction models for environmental variables and to the determination of exposure status. And the project imposes a rigorous study design and statistical methods to assure the strongest possible evidence in support of the outcome. The methods developed in this research program have applications for future environmental studies of acute health events as well as for analysis of other pesticides and their application methodologies.

Andrew Bremer, MD, Assistant Professor, Department of Pediatrics

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
Peter J. Havel, DVM, PhD, Professor, Molecular Biosciences and Nutrition

RESEARCH STUDY:  The evaluation of PC-1 as a diagnostic biomarker of insulin resistance

ABSTRACT: 
Insulin resistance and its associated conditions are important causes of morbidity and mortality worldwide. Insulin resistance has a strong genetic predisposition; however, its molecular basis in most individuals is unknown. As such, specific therapies for insulin resistance – directed at the underlying mechanism of disease – are lacking. Moreover, the lack of specific biomarkers of insulin resistance to identify at-risk individuals hinders preventive intervention. In this project, our goal is to characterize a novel specific biomarker of insulin resistance. Membrane glycoprotein PC-1 (ENPP1) is an inhibitor of the insulin receptor, and we hypothesize that it may be a major target molecule in the pathogenesis of insulin resistance. Human genetic studies, "in vitro" cell studies, and "in vivo" studies in experimental animals have all demonstrated strong associations of increased PC-1 expression and/or activity with insulin resistance. Furthermore, studies of small numbers of patients have shown that PC-1 is either over expressed or overactive in insulin target tissues of many insulin resistant subjects; therefore, analyzing PC-1 provides information regarding an individual's inherent sensitivity to insulin. The ability to study PC-1 and its role in the pathophysiology of insulin resistance in human studies is currently limited by the need for a tissue biopsy to analyze the protein, which is impractical to perform on large numbers of individuals in modern clinical practice. However, the development of a rapid blood-based assay to quantify circulating PC-1 concentrations would permit these types of evaluations. We propose that an individual’s blood level of PC-1 will directly correlate with their degree of insulin resistance, and aim to develop a novel assay to measure circulating levels of the protein. In this proposal, we will test the following hypotheses: (i) that PC-1 gene expression is increased in tissues from insulin resistant subjects; (ii) that circulating PC-1 levels are increased in insulin resistant subjects; and (iii) that blood PC-1 levels are inversely correlated with insulin sensitivity and positively correlated with other markers of insulin resistance, inflammation, and dyslipidemia. These studies will provide new information regarding the role of PC-1 in the pathogenesis of insulin resistance as well as determine the utility of using PC-1 as a novel specific diagnostic biomarker of insulin resistance, both of which may aid in the early identification and treatment of individuals at risk for diseases related to impaired insulin action.

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

Mark Underwood, MD, Assistant Professor, Department of Pediatrics

MENTORS:
Charles L. Bevins, MD, PhD, Professor, Department of Microbiology and Immunology
David A. Mills, PhD, Associate Professor, Department of Viticulture and Enology

Mark Avdalovic, MD, Assistant Professor, Department of Pulmonary and Critical Care

MENTORS:
Dallas M. Hyde, PhD, Professor and Director, California National Primate Research Center
John Robbins, MD, MS, Professor of Medicine, Department of Internal Medicine