The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases

The Center for Human Genetics

Eric Boerwinkle, Ph.D.
Professor and Director
Peter A. Doris, Ph.D.
Professor and Deputy Director
Myriam Fornage, Ph.D.
Professor
Ba-Bie Teng, Ph.D.
Professor

The Research Center for Human Genetics is using modern genomic technologies to unravel the genetic predisposition to the most common chronic diseases, such as heart disease and stroke. Cardiovascular diseases are the number one cause of sickness and death in the United States. The Texas Medical Center has a long tradition of basic and clinical research in the cardiovascular diseases. Identifying and characterizing the genes underlying cardiovascular disease susceptibility promises to offer new treatment strategies (e.g. drugs) and even prevent their occurrence altogether. The Research Center for Human Genetics uses the latest tools for large scale genomic and proteomic analyses. In addition, a major activity of the Center is the statistical and bioinformatics analysis of large-scale DNA sequence, gene expression and proteomic data.

The Director of the Center is Dr. Eric Boerwinkle. Dr. Boerwinkle is recognized for his genetic studies of cardiovascular disease and its risk factors. He has lead teams that undertook the first genome-wide analysis of hypertension (i.e. high blood pressure), diabetes, and coronary artery calcification. In diabetes, this work led to the first positional cloning of a gene for a common chronic disease (i.e., CAP10 and NIDDM). For hypertension where he directs the large Family Blood Pressure Program, Dr. Boerwinkle's laboratory has identified the ADRB2 and NBC4 genes as determinants of blood pressure levels and hypertension status in the general population. His research program combines aspects of positional, expressional and biological candidate genes for cardiovascular disease. More recently he has initiated research projects to elucidate the role of differential gene responses to commonly prescribed medications and examining inter-individual variation in response to multiple blood pressure and cholesterol lowering medications.

Dr. Peter Doris is using animal models to study factors which regulate blood pressure levels and that may lead to hypertension. Hypertension is the major reason that adults go to a physician, and is a major risk factor for heart, brain and kidney disease. Using the latest in genetic technologies, he is identifying genes that are different among strains of animals that differ in blood pressure levels and frequency of hypertension. His studies are also leading to new understandings regarding how the kidney handles salt, and how regulating salt and water balance, in turn, influences a person's blood pressure level. During the past year Dr. Doris' research group has uncovered new aspects of renal function contributing to cardiovascular disease. Using DNA chips (gene expression arrays) they have uncovered a gene transcription program operating in hypertension which results in renal injury through oxidative stress, a key mechanism by which elevated blood pressure produces progressive renal disease. Their studies on regulation of renal aspects of salt balance in hypertension have revealed abnormal regulation of the key protein that drives renal sodium transport. They have also uncovered a remarkable new function for this transport protein by showing that it also acts as a cell membrane steroid hormone receptor that activates a signaling pathway promoting cell growth. Inappropriate activation of cell growth programs during hypertension may contribute to the renal and vascular injury that link high blood pressure to end stage renal disease.

Dr. Ba-Bie Teng is leading a successful research program on the use of genetic and proteomic technologies to lower blood cholesterol, a major risk factor for heart disease. Using mechanisms that are naturally occurring, Dr. Teng's laboratory delivered therapeutic genes to mice susceptible to atherosclerosis to reduce the levels of LDL cholesterol and to remodel the arterial wall. In particular, humans make two types of a protein that transport cholesterol, Apo B-100 and apo B-48. These two proteins are products of one gene. The mRNA of apo B-100 is edited by a unique editing enzyme resulting in the production of apo B-48. Dr. Teng has initiated a collaboration with Dr. A. Khvorova at Dharmacon Research Inc., CO to engineer novel hammerhead ribozyme structures to silence apo B mRNA expression. In order to translate such findings from the bench to advances in medical practice, better and safer gene delivery systems will be necessary. In collaboration with Dr. K. Oka at Baylor College of Medicine and Dr. K. Fujise at the Institute of Molecular Medicine, her laboratory is engineering improved gene delivery vectors (e.g. new generation adenovirus-related) to investigate the prevention of hyperlipidemia and atherogenesis.

Dr. Teng's laboratory used large-scale gene expression studies to understand how the body responds to environmental factors which contribute to the increasing prevalence of atherosclerosis. In this way, the genes that influence the complex process of atherogenesis can be identified. From these studies, Dr. Teng's laboratory has recently identified a novel gene that might play a specific role in macrophage differentiation, which could regulate the development of atherosclerosis. In this way, the genes that influence the complex process of atherogenesis may be identified and new therapeutic strategies designed for the prevention and management of heart disease.

Dr. Myriam Fornage and scientists in the Research Center for Human Genetics have developed a coordinated research program on the genetics of stroke and related cerebrovascular diseases. This work is directed at understanding the molecular basis of stroke and cerebrovascular disorders using functional genomic approaches and genetic epidemiology techniques applied to both animal models and humans. Work in Dr. Fornage's laboratory employs microarray gene expression profiling and 2D gel electrophoresis proteomic analysis to identify genes and gene pathways contributing to stroke susceptibility in the stroke-prone spontaneously hypertensive rat (SHRSP), and to understand how these genes and gene pathways interact with dietary factors to modulate stroke onset. She and her colleagues have determined that kinase-mediated signaling was altered in the cortex of stroke prone rats prior to the onset of stroke. Moreover, they recently showed that unlike the stroke resistant strain, SHR, protein kinase gene expression and activity did not change in response to dietary perturbation in the SHRSP. Whether SHRSP's inability to shift expression of these kinases in response to diet contributes to pathophysiology is being investigated.

Discovery of the molecular mechanisms contributing to increased susceptibility to brain lesions in the SHRSP animal model provides the basis for investigation of these pathogenetic mechanisms in the development of human cerebrovascular disease and stroke. Dr. Fornage's laboratory investigates whether variation in the human homologues/orthologues of the genes identified in the rat model influences the risk of stroke in the human population. The cytosolic epoxide hydrolase gene is being investigated for its relationship to cardiovascular and cerebrovascular disease in humans. Such translational and collaborative research efforts that link experimental and animal model research findings to clinical and public health settings are the hallmark of The Research Center for Human Genetics. A functional polymorphism was genotyped in participants of the Coronary Artery Disease Risk Development in Young Adults (CARDIA) study and was found to be associated with coronary artery calcification, a marker of atherosclerosis and predictor of stroke.