|
|
CVRI Scientists
Prediction and prevention of cardiovascular disease
Brian L. Black, Ph.D.
Associate Professor of Biochemistry & Biophysics
Research Interests:
Cardiac and skeletal muscle development, differentiation, and function
Summary:
Congenital heart anomalies are the most common form of birth defect in the United States, affecting nearly one percent of all babies, yet the molecular and developmental basis for these defects is largely unknown. Tissues and organs form during mammalian embryonic development because of the integration of numerous signaling and transcriptional pathways. Our major goal is to define these pathways in order to understand the molecular causes of congenital anomalies and potential mechanisms for organ regeneration and repair. Using the mouse as a model system, the current work in the lab is focused on defining the pathways regulating the development of cardiac and skeletal muscle, the vascular endothelium, and neural crest. Specific projects focus on the regulation and function of genes that are known to be critical for cardiac development. These include Mef2c, Islet1, Gata4, Bmp4, and Fgf8. Each of these genes is involved in cardiac development, and we are defining their regulation and function specifically during the formation of the cardiac outflow tract, one of the most commonly and severely affected regions of the heart observed in babies. The long-term scientific goal of these studies is to define how tissues and cells are integrated during organogenesis and how cells receive and interpret positional information. We are using a combination of conditional gene knockouts, transgenic reporter assays, and fate mapping techniques in mice to define the embryological origins of the outflow tract and the reciprocal signaling between tissues that is required for proper heart development. The ultimate goal of these studies is to develop diagnostic and therapeutic interventions for birth defects of the heart and other organ systems.
|
Yuet W. Kan, M.D.
Professor of Medicine and Laboratory Medicine; Louis K. Diamond Professor of Hematology
Research Interests:
The mechanisms of globin production and exploring novel ways of inserting genes into mammalian cells; investigating newer approaches for fetal diagnosis of genetic disorders
Summary:
Our laboratory is investigating the diagnosis and treatment of diseases using recombinant DNA technology. Research is being carried out on the diagnosis of genetic diseases by testing fetal cells in the maternal circulation, thus avoiding any possible risk to the unborn child. Treatment of important genetic diseases such as sickle cell anemia and thalassemia using embryonic stem cells is being investigated, as is the treatment of coronary heart disease using gene and cell therapy.
|
John P. Kane, M.S., M.D., Ph.D.
Professor of Medicine and Biochemistry & Biophysics
Research Interests:
Structure and function of lipoproteins; genetic determinants of arteriosclerosis
Summary:
Because it has been found that faulty transport of cholesterol and other lipids is an underlying element in the development of arteriosclerosis, elucidation of molecular mechanisms involved in cholesterol transport has been a major goal of this group. This has led to the identification of previously unidentified proteins that participate in the process. Certain complexes of cholesterol and other fatty substances with proteins (lipoproteins) are known to convey cholesterol to the artery wall to initiate the formation of diseased areas (plaques) that can eventually lead to occlusion of arteries serving the heart or brain. Others (High Density Lipoproteins, HDL) have the task of removing cholesterol to protect the arteries. Understanding how HDL accomplish this task requires the discovery and characterization of previously unknown molecular complexes. Whereas it was thought that there were two species of HDL, work by this group has identified sixteen to date, detecting the different proteins that comprise each species using the technique of mass spectrometry. Studies are conducted in parallel to discover the biochemical pathways by which they are assembled, and the processes they mediate. This has led to the discovery of species that have antioxidant and anti-inflammatory activities, and another that protects humans against the organism that causes Trypanosomiasis, better known as African sleeping sickness. It has also been found that the removal of chemically injurious fatty substances from the retina involves HDL, leading to important new insights that can be applied to understanding macular degeneration, the leading cause of blindness in people over fifty years of age in the U.S.
Another goal in this laboratory is the discovery of genes related to the development of heart attacks and stroke. To accomplish this, a very large collection of human DNA, approaching 30,000 individual samples, has been assembled by the group. Each sample is accompanied by an extensive clinical history. Over twelve thousand genes have been studied thus far. Variations in twenty-one genes have now been found to be associated with heart attack and four genes have been linked to stroke. Because risk genes may interact with one another, the group is collaborating with the Los Alamos National Laboratory, using its supercomputers to develop new mathematical formulas for accomplishing this challenging task. Discovery of the genes that are linked to heart attack and stroke is expected to lead to new strategies for prevention and treatment of those diseases. Other targets of the genetic research by this group that are related to heart disease are diabetes, HDL deficiency states, other lipoprotein disorders, and macular degeneration. Six previously unrecognized diseases caused by defective genes have been discovered in this effort.
|
Theodore W. Kurtz, M.D.
Professor of Laboratory Medicine
Research Interests:
Molecular genetics of complex disease, animal models of hypertension and the metabolic syndrome, transcription modulating drugs
Summary:
Hypertension (high blood pressure) affects 60 million people in the United States and is a major cause of stroke, kidney failure, and heart disease. Patients with hypertension are also at increased risk for diabetes and often have multiple risk factors for cardiovascular disease in addition to increased blood pressure. Our research is designed to shed light on why hypertension and the associated risks for diabetes and cardiovascular disease run in families. The results of these genetic studies are used to guide development of new approaches to therapy and to identify new opportunities for preventing the development of diabetes and cardiovascular disease in high risk patients.
|
Pui-Yan Kwok, M.D., Ph.D.
Professor of Dermatology, Henry Bachrach Distinguished Professor of Cardiovascular Genetics
Research Interests:
Genetic analysis of complex traits, DNA technology development
Summary:
The overall goal of our research is to develop the tools for genetic analysis of whole genomes and apply these tools to elucidate the genetic factors associated with common human diseases. Our group developed a number of DNA analytical assays and was part of the International Haplotype Map Consortium that recently constructed the comprehensive genetic (haplotype) maps of the human genome with close to a million markers. This map is freely available to all researchers to map genes involved in common human diseases.
Currently, we are developing efficient methods for molecular haplotyping and DNA sequencing. We are applying state-of-the-art molecular genetic tools to identify genetic factors associated with diverse complex human traits such as longevity, hypertension, sudden cardiac arrest, hemorrhagic stroke, psoriasis, lupus, and kidney transplantation outcome. We are also conducting studies to identify genetic factors associated with drug response to chemotherapy in colon cancer
|
Mary J. Malloy, M.D.
Clinical Professor of Pediatrics and Medicine
Research Interests:
Molecular mechanisms in lipoprotein metabolism; genetic basis of metabolic disorders of lipoproteins and of arteriosclerosis
Summary:
Because it has been found that faulty transport of cholesterol and other lipids is an underlying element in the development of arteriosclerosis, elucidation of molecular mechanisms involved in cholesterol transport has been a major goal of this group. This has led to the identification of previously unidentified proteins that participate in the process. Certain complexes of cholesterol and other fatty substances with proteins (lipoproteins) are known to convey cholesterol to the artery wall to initiate the formation of diseased areas (plaques) that can eventually lead to occlusion of arteries serving the heart or brain. Others (High Density Lipoproteins, HDL) have the task of removing cholesterol to protect the arteries. Understanding how HDL accomplish this task requires the discovery and characterization of previously unknown molecular complexes. Whereas it was thought that there were two species of HDL, work by this group has identified sixteen to date, detecting the different proteins that comprise each species using the technique of mass spectrometry. Studies are conducted in parallel to discover the biochemical pathways by which they are assembled, and the processes they mediate. This has led to the discovery of species that have antioxidant and anti-inflammatory activities and another that protects humans against the organism that causes Trypanosomiasis, better known as African sleeping sickness. It has also been found that the removal of chemically injurious fatty substances from the retina involves HDL, leading to important new insights that can be applied to understanding macular degeneration, the leading cause of blindness in people over fifty years of age in the U.S.
Another goal in this laboratory is the discovery of genes related to the development of heart attacks and stroke. To accomplish this, avery large collection of human DNA, approaching 30,000 individual samples, has been assembled by the group. Each sample is accompanied by an extensive clinical history. Over twelve thousand genes have been studied thus far. Variations in twenty-one genes have now been found to be associated with heart attack and four genes have been linked to stroke. Because risk genes may interact with one another, the group is collaborating with the Los Alamos National Laboratory using its supercomputers to develop new mathematical formulas for accomplishing this challenging task. Discovery of the genes that are linked to heart attack and stroke is expected to lead to new strategies for prevention and treatment of those diseases. Other targets of the genetic research by this group that are related to heart disease are diabetes, HDL deficiency states, other lipoprotein disorders, and macular degeneration. Six previously unrecognized diseases caused by defective genes have been discovered in this effort.
|
Ethan J Weiss, M.D.
Assistant Professor of Medicine
Research Interests:
Genetic regulation of blood clotting in mice; sex differences in blood clotting.
Summary:
The blood clotting system is centrally important as a means to protect from blood loss. To do so, the system must be sensitive to disruptions in blood vessels. We know from naturally occurring human genetic mutations and experiments in animals that a deficiency of function or amount of clotting related proteins leads to bleeding. Yet the system must also be specific. There is an equal body of evidence that unregulated or increased propensity to form blood clots leads to deleterious clot formation such as occurs in heart attacks, strokes, and blood clots in large veins. The clotting system therefore must maintain exquisite balance between tendency toward clotting and tendency toward bleeding. Minor changes in concentration or function of a host of known and countless unknown proteins can tip the balance in either direction. Primarily, we use the mouse as a model system to define genetic regulation of blood clotting in an attempt to define genetic changes that might predispose to tipping the balance in either direction. We hope to learn more about the molecules and pathways that lead to clot formation. We hope to define novel molecules or pathways that regulate clotting or interact with known clotting pathways. We are particularly interested in how male or female sex affects clotting in animals. We know that women are 1) less likely to form clots in clotting tests and 2) are protected as compared to men in diseases associated with increased clotting like heart attacks. This tells us that women may have evolved a system with a more favorable balance between clotting and bleeding. We hope to learn how and why that may be. Ultimately, we hope to identify new risk factors for bleeding disorders as well as the clotting associated diseases such as heart attack and stroke. Furthermore, we hope that by understanding the biological mechanisms underlying such risks, we might eventually identify novel drug targets aimed at treating or preventing bleeding, stroke, heart attack or blood clots.
|
|
|
