Research Opportunities with Mario Castro, MD, MPH

Professor, Department of Medicine: Dr. Castro’s research projects are in the area of pathogenesis of asthma and health-care delivery issues in asthma. He has a prospective cohort study, called the Respiratory synctial virus (RSV) Bronchiolitis in Early Life (RBEL) study, sponsored by the NIH, which is seeking to understand the genetic, biologic, and immunologic determinants of asthma in infants hospitalized with RSV bronchiolitis. He also has a NIH sponsored grant to evaluate non-invasive measurement of airway remodeling in patients with severe asthma as part of the NHLBI Severe Asthma Research Program. As part of this program he has recently received funding to start a longitudinal study of severe asthma in adults and children with special focus on airway remodeling changes over time. In addition, our laboratory runs the Clinical Core of a NIAID-sponsored Allergic Diseases Cooperative Research Centers (AADCRC) grant on the Molecular and Cellular Mechanisms of Asthma at Washington University School of Medicine. He also has a NIH sponsored grant to study a c-kit mast cell inhibitor, imatinib, in severe asthma in collaboration with colleagues at Brigham and Women’s Hospital and University of Wisconsin-Madison. His lab also has an American Lung Association Asthma Clinical Research Center and NIH sponsored AsthmaNet center which aim to conduct large multicenter studies to develop new approaches to asthma management and treatment.

Research Opportunities with F. Sessions Cole, MD

Professor, Department of Pediatrics: Since the original description of deficiency of the pulmonary surfactant in premature newborn infants by Avery and Mead in 1959, respiratory distress syndrome has most commonly been attributed to developmental immaturity of surfactant production. The pulmonary surfactant is a mixture of phospholipids and protein synthesized, packaged, and secreted exclusively by type 2 pneumocytes that line the distal airways. This mixture forms a monolayer at the air-liquid interface in the alveolus that lowers surface tension at end expiration of the respiratory cycle and thereby prevents atelectasis and ventilation-perfusion mismatch. Although persistence of respiratory morbidity has been attributed to developmental pulmonary immaturity, oxygen toxicity, and barotrauma, the fact that only a fraction of infants (5%-25%) develops these problems strongly suggests that genetic factors play an important role. By ameliorating pulmonary dysfunction immediately after birth, surfactant replacement therapy has unmasked the contribution of genetic causes of respiratory distress syndrome to morbidity and mortality in infancy. In addition, studies of different ethnic groups, gender, targeted gene ablation in murine lineages, and recent clinical reports of monogenic causes of neonatal respiratory distress syndrome have strongly suggested that genetic mechanisms contribute significantly to risk of respiratory distress syndrome in newborn infants. In contrast to developmental causes of respiratory distress which may improve as infants mature, genetic causes result in both acute and chronic (and potentially irreversible) respiratory failure. Using high throughput, complete resequencing, genotyping, large population- based and case-control cohorts, and model systems, Dr. Cole’s laboratory has focused on discovery of candidate genes and gene pathways that account for the heritability of neonatal respiratory distress syndrome due to surfactant deficiency.

Research Opportunities with Sharon Cresci, MD

Assistant Professor, Department of Medicine: Dr. Cresci’s research efforts are focused on the association of genetic variation with clinical outcomes in patients with cardiovascular disease and on the role of genetic variation in the variable response to pharmacologic treatment (i.e. Pharmacogenomics) of cardiovascular disease. She has specific interest in patients with both diabetes mellitus (DM) and coronary artery disease. The ultimate goal of her research is to personalize each patient’s treatment based on their genotype. She is the PI or an active investigator on several NIH-sponsored studies, is a collaborator on the NHLBI-sponsored Exome Sequencing Program (ESP) Myocardial Infarction (MI) Project Team, and is the Director of the Applied Genomics Core Laboratory for the TRIUMPH (Translational Research Investigating Underlying disparities in acute Myocardial infarction Patients’ Health status) cohort.

There are several ongoing projects in Dr. Cresci’s laboratory that trainees could participate in: Project 1: Association of PPAR-pathway gene polymorphisms with diabetic outcomes in BARI 2D. This project seeks to comprehensively investigate the genetic and pharmacogenetic associations of PPAR-pathway variants (genotypes and/or haplotypes) in a population with type 2 DM and coronary artery disease that has been extensively phenotyped for diabetes-related and cardiovascular traits at baseline and follow-up data including medications. Project 2: Genomic variants associated with angina and health status outcome after MI. This project has three AIMS: 1) To define the genetic contribution to the observed inter-individual variation in post- MI angina. 2) To identify non-genomic factors that may potentially moderate the effects of the genetic variants identified in AIM 1. 3) To test the feasibility of translating – into ‘real world practice’ – a prognostic modeling tool (PRISMTM) that includes genetic variants identified by AIM 1, to predict health status response to post-MI treatment. Project 3: Understanding phenotypic variability in hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy (HCM), occurring in 1/500 adults, is caused by nearly 1000 distinct genetic mutations inherited in an autosomal dominant pattern. This project is a longitudinal, prospective cohort study of HCM patients and their first-degree blood relatives. The goal of this project is to define genetic predictors of severity and progression of HCM.

Research Opportunities with Victor Davila-Roman, MD

Professor of Medicine, Anesthesiology and Radiology, Department of Medicine. Hypertension (HTN), one of the most prevalent diseases in the industrialized world, affects 65 million Americans. Hypertensive heart disease (HHD), the most common cardiac sequelae resulting from longstanding HTN, is manifested by development of left ventricular hypertrophy (LVH, prevalence 25-50% of HTN), left ventricular diastolic dysfunction (LVDD, prevalence 25-50% of HTN) and/or dilated cardiomyopathy/heart failure (DCM/HF, incidence 0.5 million yr). The molecular and/or genetic mechanisms responsible for the development of LVH and/or HHD have not been well characterized. Alterations in myocardial substrate utilization (i.e. decreased myocardial fatty acid [FA] utilization and oxidation) are important determinants of the presence/development of LVH in animal models of pressure-overload and in humans. Metabolic genes such as peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC1α), a coactivator for nuclear receptors, and peroxisome proliferator-activated receptor-α (PPARα), a transcriptional regulator of myocardial FA transport and β-oxidation enzymes, have been implicated in the development of LVH and of DCM/HF.

The work in our laboratory is designed to test the hypothesis that genetic variations in metabolism genes (such as PGC1α and PPARα) influence the phenotypic expression (i.e. presence and severity) of LVH in humans, either directly or through its interaction with other metabolism genes. This hypothesis is being tested in silico by use of a rich dataset (over 1800 subjects who have been exquisitely phenotyped and genotyped). The study design is a genotype-phenotype, case-control association study. Issues related to environmental selection and/or genotype-phenotype heterogeneity will be addressed by the case-control study design (patients with hypertensive heart disease and age-, gender-, race-matched normal controls) to provide sufficient statistical power (>0.9) to identify SNPs and/or haplotypes associated with HHD. These studies will expose the student to a number of in vitro (gene sequencing) and in silico methods, analysis software programs, and/or online genomic databases such as: SAS, Phred, Phrap, Polyphred, Consed, PHASE, SeattleSNP, UCSC Genome Browser, MIDAS, Ingenuity Pathway Analysis, and others. The student will also interact with wet lab researchers to design and test new genotyping assays for SNPs of interest identified from the in silico analyses. This is an important study that may shed significant insight as to the molecular and/or genetic mechanisms mediating hypertensive heart disease.

Research Opportunities with Lisa de las Fuentes, MD, MS

Assistant Professor, Department of Medicine: Dr. de las Fuentes’ ongoing clinical and translational research projects investigate the molecular and genetic modifiers of hypertensive cardiovascular disease phenotypes in humans. A graduate of the WUSM Genetic Epidemiology Master’s of Science (GEMS) program, she is particularly interested in the genetic, metabolic, inflammatory, and environmental modulators of left ventricular hypertrophy, left ventricular systolic and diastolic dysfunction, and vascular hypertrophy. One focus of Dr. de las Fuentes’ research is to tease apart the complex gene-gene interactions among genes involved in myocardial fatty acid metabolism. Long- chain fatty acids are an essential source of energy for the heart. Recent evidence suggests that interactions among genes in fatty acid metabolism regulatory pathways play an important role in the etiology of cardiovascular diseases, especially left ventricular hypertrophy and diabetic cardiomyopathy. Thus, research efforts are centered on identifying variants within myocardial and systemic metabolism gene that associated with the presence and severity of hypertensive heart disease phenotypes in a biracial cohort and to further evaluate the modifying factors of latent hypertensive heart disease-related phenotypes by exploring gene-gene and gene-environment interactions. Her research takes advantage of sophisticated statistical techniques including Independent Component Analysis for multivariate data-reduction and Bayesian Network modeling to evaluate complex within-gene and gene-gene interactions. As Co-Director of the Cardiovascular Imaging and Clinical Research Core Laboratory (CIRCL) and a clinical cardiologist at Washington University, she has expertise in a variety of imaging modalities, clinical assessments, and laboratory assays used for characterization of cardiac, vascular, metabolic, and inflammatory phenotypes, including echocardiography, vascular sonography, multidetector computed tomography (MDCT), myocardial positron emission tomography (PET) imaging, and non-invasive measurement of vascular compliance.

Research Opportunities with Brian Gage, MD, MSc

Professor, Department of Medicine: Dr. Gage’s clinical research focuses on several related areas: atrial fibrillation, thrombosis, pharmaco- epidemiology and pharmacogenomics. He has devised clinical prediction rules (e.g. CHADS2) of adverse events in the atrial fibrillation population and conducted clinical studies. Under the aegis of NHLBI R01 HL074724 and R01 HL097036, Dr. Gage has been studying how to use genetic and clinical markers to predict and prevent adverse events in patients who take warfarin. The resulting databases and archived DNA from 1,850 patients form an ideal resource for trainees in clinical research. Trainees will quantify determinants of warfarin dose, and test the hypothesis that they will be able to estimate a safe warfarin dose a priori, rather than by using the current system of trial-and-error warfarin dosing. By identifying polymorphisms in genes that affect the pharmacokinetics and pharmacodynamics of warfarin, trainees will derive and validate novel dosing algorithms and predictors of thrombosis. Using the National Registry of Atrial Fibrillation (NRAF) II, traineesalso can quantify how clinical and laboratory factors affect the risks of hemorrhage and thrombosis in the atrial fibrillation population.

Research Opportunities with C. Charles Gu, PhD

Associate Professor, Division of Biostatistics: Dr. Gu’s research activities encompass a wide spectrum across designing, conducting and analyzing genetic studies of complex diseases. He is an active investigator on several multi-center genetic epidemiological studies of such complex traits as heart disease, genetic response to exercise, blood pressure and hypertension, left ventricular hypertrophy, and pharmacodynamic factors regulating drug therapy. His research deals with issues related to mapping complex disease genes by large-scale GE studies. His recent research interests, funded by NHLBI, include genome-wide association (GWA) studies of blood pressure, hypertension, and echocardiographic measures of the heart (especially left ventricular hypertrophy). Dr. Gu has extensive experience in developing novel methodologies useful for detecting complex disease genes and characterizing their functions. His methodological research includes algorithm for study design optimization and high- dimensional genomic data analysis; multivariate data-reduction techniques (PCA, clustering analysis, Independent Component Analysis etc.) to extract hidden structure in genotype-phenotype association. The overarching interest of Dr. Gu’s research is translating complex high dimensional genetic/clinical data into applicable scientific knowledge to improve public health.

Research Opportunities with Patrick Jay, MD

Associate Professor, Departments of Pediatrics and Genetics: The Jay lab is interested in dissecting the multifactorial basis of congenital heart disease in a mouse model. Mutations of the cardiac transcription factor Nkx2-5 cause heart defects in man and mouse, but other genetic and environmental factors influence the risk of specific mutant phenotypes. These factors may suggest viable targets to prevent disease. The lab has developed a unique infrastructure and resources to map QTLs and analyze factors like maternal age that affect the susceptibility of cardiac developmental pathways to Nkx2-5 mutation. Ongoing work in the lab uses genetic, genomic and epigenetic methods to identify the underlying genes and pathways. Opportunities exist to develop interdisciplinary strategies and quantitative solutions to aclinically important problem in developmental biology.

Research Opportunities with Douglas Mann, MD

Professor, Department of Medicine: Dr. Douglas Mann is Lewin Professor and Chief of the Cardiovascular Division at Washington University School of Medicine. His primary area of research is the molecular and cellular basis of heart failure, with a particular emphasis on the maladaptive role of inflammatory mediators and innate immunity in disease progression in the failing heart. His laboratory has focused on tumor necrosis factor (TNF) signaling in cardiac myocytes and cardiac fibroblasts, as well as the impact of TNF signaling in regulating cardiac structure and function in the intact heart using genetically modified mice. Collectively, these studies have suggested that TNF signaling contributes to disease progression in the heart. More recent studies have begun to use a bioinformatics approach to identify novel targets of disease progression in heart that are downstream from innate immune signaling in the heart. His second research interest is focused on the adaptive (beneficial) role of inflammatory mediators and innate immunity in the mammalian heart. These studies have identified a potentially important role for tumor necrosis factor receptor adaptor factor 2 (TRAF2) as scaffolding protein that mediates the cytoprotective effects of TNF in the adult heart.

Research Opportunities with Aubrey Morrison, MD

Professor, Department of Medicine: Dr. Morrison is a Professor of Medicine and developmental Biology and the Director of the training program in Nephrology of the department of medicine. With the cloning of the gene for the inducible cyclooxygenase (COX-2), it was realized that the mRNA for COC-2 had a 2.2 kB 3’UTR which like many early response genes contain cis-acting elements which appear to be involved in both translational efficiency and message stability. His research has focused on identifying the trans-acting factors which bind to a canonical sequence AUUUA present in the COX-2 message and determine which sequences control mRNA stability and which control mRNA translational efficiency using deletion mutagenesis and expression of these constructs in cells. He has also used this canonical sequence as “bait” to pull down nuclear proteins that bind to this sequence in vitro with high affinity and probe their function in cells using mutagenesis of the active site of these proteins. In addition he have evaluated the mechanisms by which the MAP kinase family of proteins can lead to cyclooxygenase product formation in response to pro-inflammatory cytokines and the potential role of these kinases in the post- translational modification of the trans-acting factors which alters their function. As a faculty member he has trained 23 post-doctoral candidate including PhD’s and MD’s (clinical fellows) and two pre-doctoral students including one MD/PhD student. Many of these have assumed faculty positions in Universities nationally and internationally as well as key positions in the pharmaceutical industry. He also serves on the National Advisory Committee of the Harold Amos Minority Faculty Development Program of the Robert Wood Johnson Foundation. Finally he is the Chair of the Committee on Research Integrity for Washington University.

Research Opportunities with Jeanne Nerbonne, PhD

Alumni Endowed Professor of Molecular Biology and Pharmacology, Department of Developmental Biology: Research in this laboratory explores the molecular, cellular and systemic mechanisms involved in the dynamic regulation of cardiac and neuronalmembrane excitability. Investigators in this laboratory exploit a combination of biochemical, electrophysiological, immunohistochemical and molecular genetic techniques in studies focused on characterizing the voltage-gated ion channels expressed in different cell types, identifying the molecular correlates of these channels, and delineating the molecular mechanisms controlling channel expression, distribution and functioning.

A major goal of ongoing work in the Nerbonne laboratory is to define the physiological roles and the molecular determinants of the various Ca++-independent, voltage-gated K+ (Kv) channels that control the heights and durations of action potentials in the mammalian myocardium. Using a variety of molecular genetic strategies and proteomics, ongoing studies are aimed at defining the roles of Kv channel accessory subunits and regulatory proteins in controlling the functional cell surface expression and the biophysical properties of Kv channels in the normal heart. Similar approaches are exploited in studies aimed at defining the molecular determinants of myocardial voltage-gated Na+ (Nav) channel expression and functioning. Additional studies are exploring the molecular mechanisms underlying Kv and Nav channel remodeling in the hypertrophied and failing heart and in other myocardial diseases associated with cardiac rhythm disturbances.

The other major focus of the research in this laboratory is on delineating the molecular mechanisms that control the expression, localization and functioning of neuronal Kv and Nav channels, which are key determinants of excitability, functioning to control resting membrane potentials, action potential waveforms, repetitive firing, the responses to synaptic inputs and synaptic plasticity. Ongoing studies are exploring the molecular basis of functional neuronal Kv and Nav channel diversity and the molecular mechanisms controlling the expression, trafficking, localization and biophysical properties of these channels.

Research Opportunities with Michael A. Province, PhD

Professor of Genetics and Biostatistics, Department of Genetics; Director, the Division of Statistical Genomics.: Dr. Province is a Professor and the Chair of the Division of Statistical Genomics (in the Department of Genetics) and a Professor in the Division of Biostatistics. He received a PhD in mathematics from Washington University in 1987. He is a theoretical as well as an applied statistical geneticist who specializes in complex trait human gene discovery and validation, pathway analysis, and the design and conduct of multicenter studies and clinical trials, especially family and genetic studies. He has published over 220 applied or theoretical scientific publications. He has made most of his methodological contributions to population and statistical genetics. He has developed longitudinal, growth curve pharmacogenetic models of treatment effect, Poisson-Process genetic models, frailty models for age-at- onset phenotypes, regression tree/recursive partitioning linkage analysis methods, meta-analysis linkage procedures, and novel Sequential Multiple Decision Procedures to simultaneously identify all promising areas in a genome scan while controlling for overall type I and type II error rates. He has also developed a generalized systems biology model and program for performing multivariate and multilocus genetic analysis (SEGPATH). He is the Coordinating Center PI of several national, and international multicenter genetic studies, including the NHLBI Family Heart Study (heart disease genetics), the SCAN Study, the GOLDN Study (lipid pharmacogenetics), and the Long Life Family Study (longevity genetics). His latest research interests span a spectrum of GWA studies.

Research Opportunities with D. C. Rao, PhD

Professor and Director, Division of Biostatistics; Professor in the Departments of Genetics, Psychiatry, and Mathematics: The core research program in Dr. Rao’s lab deals with both methodological research in genetic epidemiology and statistical genetics as well as substantive applied research in cardiovascular disease with particular emphasis on blood pressure and hypertension, lipids, and metabolic syndrome. Ongoing research, supported by several NIH grants, provides opportunities at both theoretical and applied levels. Several projects involve close interaction and collaboration with a number of research groups at the Washington University Medical Center as well as groups of investigators across the country. A number of theoretical and applied problems are addressed involving genome-wide association (GWAS) analysis of common complex disease traits for identifying part of the missing heritability: gene-gene and gene-environment interactions in the longitudinal Framingham Heart Study data (FHS-SHARe); gene-lifestyle interactions, pleiotropy and pathway analyses in large multi-ethnic cohorts participating in an international consortium as part of CHARGE; and rare and low frequency genetic variants for hypertension through exome sequencing, among other related projects. Together, they offer promising approaches for dissecting the genetic architecture of complex diseases and disease-related risk factors.

Research Opportunities with John P. Rice, PhD

Professor, Department of Psychiatry, and Division of Biostatistics: Dr. Rice has a PhD in mathematics and did post-doctoral work at Washington University in genetic statistics. His current research interests include methods development in genetic epidemiology and family study techniques, and the collection and analysis of family data on the affective disorders, schizophrenia, smoking, alcoholism and other substance-use disorders. Research opportunities include: (1) participation in ongoing genetic studies; (2) statistical methods development in genetic epidemiology; and, (3) analysis of available data in the NIMH, NIDA, and NIAAA repositories.

The area of possibly greatest interest to our trainees is developing new statistical methods. Dr. Rice has a long history of methodologic contributions in the area of quantitative methods for genetic analysis. Methodologic work includes: (i) the development of new measures of linkage disequilibrium to define SNPs for association analysis; (ii) the use of the logistic regression model to incorporate covariates into genetic analysis; and (iii) the incorporation of follow-up data into genetic models to allow for diagnostic evaluations at multiple points in time. He continues to apply these new techniques to a number of currently existing data sets. His emphasis has been shifting from linkage analysis using several hundred repeat markers to association analysis using 1 million SNPs in GWAS (Genome-Wide Association Studies). He is currently active with several GWAS initiatives for alcoholism, nicotine dependence and bipolar disorder. This new trend in the genetics of complex traits represents many challenges in data management and in analysis. He will soon receive exome sequence data on five distantly related members in a single Bipolar pedigree. The best way to analyze these data is unclear and will require methodologic work.

Research Opportunities with Treva K. Rice, PhD

Research Associate Professor, Division of Biostatistics, and Department of Psychiatry: Dr. Rice’s general research centers on uncovering the genes and familial environmental determinants for cardiovascular diseases and associated risk factors such as obesity, diabetes, hypertension, lipids, lipoproteins, and respiratory fitness. Of current interest are general methodological problems associated with “environmental intervention” data. Alternative methods that index such longitudinal “response” data (e.g. growth curves and profile analysis) are being investigated. Other multivariate interests include pleiotropic (single gene affecting multiple traits) and/or oligogenic (multiple genes affecting single trait) models. All methods are applied to family intervention studies and center on analysis of familial aggregation and genetic associations. Dr. Rice is an active investigator in numerous multi-center family and genetic studies such as (1) the HERITAGE Family Study exploring familial factors underlying the response to endurance exercise training on metabolic and hormonal traits and (2) the GenSalt study of dietary sodium and potassium intervention on hypertension in rural Chinese families. The available genotype data in both family studies include genome-wide microsatellite markers for linkage analysis, and candidate genes and genome-wide association (GWA) marker panels for association analysis. Dr. Rice also plays active roles in training and teaching by serving as a research mentor for graduate students and course master for the fundamentals of genetic epidemiology.

Research Opportunities with Clay F. Semenkovich, MD

Professor, Department of Medicine; Herbert S. Gasser Professor, Chief of the Division of Endocrinology, Metabolism and Lipid Research, Professor, Departments of Medicine and Cell Biology & Physiology: Dr. Semenkovich and the investigators in his laboratory are interested in lipid metabolism and how it promotes atherosclerosis in the setting of obesity, insulin resistance and diabetes. Their work is translational, spanning cultured cells, animal models and humans. Fats are partitioned to tissues in highly regulated ways. Excess lipids directed to adipose tissue are stored and lead to obesity, a disorder associated with diabetes, insulin resistance, and heart disease. They engineered mice with ectopic and inducible expression of uncoupling protein-1 (UCP-1) in specific tissues. UCP-1 is an inner mitochondrial anion transporter that uncouples respiration and oxidative phosphorylation. These animals are being used to study the role of metabolism in age-related diseases such as atherosclerosis and hypertension.

Fatty acid metabolism is controlled in part by the nuclear receptor perioxisome proliferator-activated receptor alpha (PPARalpha). They have demonstrated a role for this receptor in atherosclerosis, diabetes and hypertension in animal models. Using tissue-specific inactivation of the rate-limiting enzyme in atherosclerosis, fatty acid synthase (FAS), they have also shown that FAS generates an endogenous ligand responsible for PPARalpha activation. Ongoing studies are defining how FAS and PPARalpha interact to affect metabolism.

Up to a quarter of Americans have some combination of abnormal lipids, high blood pressure, elevated blood sugar, and excess abdominal fat. Collectively, these conditions constitute the metabolic syndrome (MetS), which confers considerable risk for frank diabetes and cardiovascular disease. They have shown that a mutation in the kinase ATM, known to be responsible for the cancer-prone disease ataxia telangiectasia, contributes to features of the MetS in mice. Low dose, intermittent administration of the anti-malarial drug chloroquine activates ATM and improves metabolic abnormalities in mice. Mechanistic studies in animal models and clinical trials in humans are testing the hypothesis that ATM activation ameliorates the MetS.