CVRI Scientists

Metabolism, obesity and metabolic diseases

Kaveh Ashrafi, Ph.D.
Associate Professor

Research Interests:
Genetics of fat regulation and neurobiology of feeding behavior

Summary:
Obesity is a major risk factor associated with many diseases including diabetes, cardiovascular and gastrointestinal diseases, arthritis, and certain forms of cancers. The prevalence of obesity reflects the combination of high calorie diets with sedentary lifestyles. However, genetic predispositions play profound roles in determination of an individual's fat. How genetic and environmental factor interact to determine fat content and how excess fat accumulation causes disease processes are poorly understood. To identify genes that underlie fat regulation we use the genetically tractable worm C. elegans. This system has allowed us to discover novel fat regulatory pathways, compounds that alter fat content, and probe the neural circuits that regulate fat and feeding.

Andy Chang, Ph.D.
Assistant Professor

Research Interests:
Acute oxygen and metabolic sensing in cardiopulmonary regulation and disease

Summary:
To maintain optimal oxygen delivery to tissues, there is constant regulation of respiratory and cardiovascular systems by mechanisms that act on different time scales. On a fast time scale, a small chemosensory organ called the carotid body senses decreases in blood oxygen to increase breathing within seconds. The carotid body can also regulate cardiovascular function acutely, and carotid body hyperactivity contributes to disease progression in hypertension, heart failure, and metabolic syndrome. Using the mouse as our primary model, we aim to identify the molecular mechanisms that mediate the carotid body's ability to detect changes in blood oxygen as well as other metabolic signals, such as carbon dioxide and acid. One long term goal is to apply this knowledge to manipulating carotid body activity in the treatment of cardiovascular disease and metabolic syndrome.

Ajay Chawla, M.D., Ph.D
Professor

Research Interests:
Immune determinants of metabolism and regeneration; Nuclear receptor signaling in innate immune cells

Summary:
Across species, the aberrant activation of the innate immune system has been linked to pathogenesis of metabolic, inflammatory and degenerative diseases. However, the molecular pathways by which innate immune cells coordinate these diverse programs remain poorly understood. Our laboratory aims to elucidate the regulatory role of nuclear receptors and co-activator proteins in innate immune activation, and the importance of these pathways in paradigms of health and disease, such as obesity, diabetes, cancer and tissue regeneration.

Rahul C Deo, M.D., Ph.D.
Assistant Professor

Research Interests:
Genetic variants underlying cardiovascular and metabolic disease

Summary:
We are now surrounded by an unprecedented amount of information about the human genetic variation that influences who will develop cardiovascular disease. Although more variants are likely to be found, we can now turn our attention to deciphering the mechanisms by which this variation in DNA ultimately governs the differences from individual to individual. My research is focused on tackling this problem in several ways, combining experimental and emerging computational approaches to take advantage of the enormous amount of new molecular information in the public domain. Specifically, I hope to adapt the sorts of statistical learning tools used in finance and engineering (and consumer marketing!) to narrow the list of likely genes that determine our cholesterol levels. Guided by this information, I hope to move to the experimental laboratory to then decipher how individual variation affects the amount of these genes, and to break down how common environmental exposures influence their levels. My ultimate aim is to identify potential new drug targets and develop new means to classify patients according to their "molecular fingerprints" under stress.

David G Gardner, M.D.
Professor in Residence

Research Interests:
Cardiovascular endocrinology, natriuretic peptides, natriuretic peptide receptors, vitamin D, nuclear hormone receptors, growth and hypertrophy in cardiovascular system and kidney, obesity-related cardiomyopathy.

Summary:
Our laboratory is interested in understanding the role that hormones play in the control of growth and function in the cardiovascular system (heart and blood vessels). We are particularly interested in vitamin D and the natriuretic peptide hormones, two classes of hormones that have beneficial effects on cardiovascular function.

John P Kane, M.S., M.D., Ph.D.
Professor

Research Interests:
Structure and function of lipoproteins; genetic determinants of arteriosclerosis

Summary:
The Kane laboratory focuses on the discovery of the native structures of lipoproteins ( proteins that carry cholesterol so that we can better understand how they are involved in the development of heart disease and stroke. We are also active in the discovery of alterations in genes that lead to heart disease and stroke.

Ronald M Krauss, M.D.
Adjunct Professor

Research Interests:

Summary:
Lipoprotein metabolism and risk of cardiovascular disease

Despite recent advances in treatment, cardiovascular disease (CVD) remains the leading cause of death in the US and will soon achieve this status globally. Our group's research is aimed at addressing three major challenges for reducing this enormous disease burden. First, standard diagnostic procedures do not identify a high proportion of children and adults who are at risk for CVD. We have developed and implemented a sophisticated new procedure that, by analyzing individual lipoprotein particles, provides more specific information than that afforded by ordinary cholesterol testing, and hence is capable of improving both the assessment and management of CVD risk. Second, dietary and lifestyle guidance has failed to substantially impact CVD risk factors, particularly those related to overweight and obesity. We have demonstrated that carbohydrate restriction can reverse the high risk lipid profile found in a high proportion of overweight and obese individuals even without weight loss, and that this effect is independent of saturated fat intake. These findings have helped support dietary guidelines that place a greater emphasis on limiting refined carbohydrates than fats. Third, despite the awareness of wide interindividual variability in response to treatments aimed at reducing CVD risk, the potential benefits of applying genomic tools for developing personalized approaches for maximizing CVD risk reduction have not been realized. A major component of our research program has been the application and development of genomic methodology for dissecting genetic influences on the therapeutic responses to statins, the most widely prescribed class of drugs for reducing CVD risk.

Dengke Ma, Ph.D.
Assistant Professor

Research Interests:
Genetic approaches to understanding physiology and diseases, oxygen-modulated metabolism and behavior; brain-heart-lung interaction and interoception; ischemic disease and tolerance; novel genes and pathways evolutionarily conserved in C. elegans and humans.

Summary:
As humans, we drink when thirsty, eat when hungry, and increase our breathing and heart rates when short of oxygen. How do we (our bodies) know when and how to respond to changes in internal bodily states (e.g. loss of nutrient or oxygen)? Genes and traits that facilitate such underlying mechanisms confer great advantages for animal survival and are strongly selected for during evolution. Using both C. elegans and tractable mammalian model systems, we seek to understand the molecular, cellular and neural circuit basis of how animals sense and respond to changes in internal metabolic and energetic states to elicit behavior and maintain homeostasis. Dysfunction of these fundamental physiological processes leads to many disorders, including obesity, diabetes, neurological and cardiovascular diseases.

Robert W Mahley, B.S., Ph.D., M.D.
Director

Research Interests:
I. Plasma lipoprotein metabolism Hepatic and intestinal origin of plasma lipoproteins; Apolipoprotein structure and function, especially apolipoprotein (apo) E and apoB; Characterization of cell surface receptors for lipoproteins; Role of the liver in cholesterol homeostasis. II. Relationship of plasma lipoproteins to the development and progression of atherosclerosis Role of diet in progression of coronary artery heart disease; Effect of apoE production in the artery wall on inhibition of atherogenesis. III. Role of apoE in the nervous system Effect on peripheral nerve injury and repair; Role in the pathogenesis of Alzheimer's disease; Effect on neuronal cytoskeleton. IV. Turkish Heart Study Director of epidemiological study to determine the risk factors responsible for coronary artery disease in Turkey; Characterization of genetic polymorphisms responsible for low HDL-C levels and metabolic syndrome in Turks; Co-director of physician continuing education program for Turkish doctors and medical students in the area of cardiovascular disease.

Summary:
My research has focused on the structure and function of apolipoprotein (apo) E, specifically its critical role in cholesterol homeostasis and atherosclerosis and, more recently, in Alzheimer's disease and neurodegeneration. ApoE regulates the clearance of plasma lipoproteins by mediating their binding to lipoprotein receptors and is also involved in peripheral nerve regeneration, lipid transport in the nervous system, and cytoskeletal stability and neurite extension and remodeling. A goal of our research is to develop a drug that will block the detrimental effects of apoE4 in cardiovascular and neurodegenerative disorders.

Mary J. Malloy, M.D.
Senate Emeritus

Research Interests:
Molecular mechanisms in lipoprotein metabolism; genetic basis of metabolic disorders of lipoproteins and of arteriosclerosis

Summary:
My chief research foci are the discovery of previously unknown disorders that affect the metabolism of cholesterol and other lipids, and the discovery of genes that are associated with the risk of heart attack and stroke. Identification of these diseases and genetic markers of risk will lead to improved prevention and treatment of coronary disease and stroke.

Takashi Mikawa, M.S., Ph.D.
Professor

Research Interests:
Morphogenesis, development, body axis, patterning, cell-to-cell communication, cell architecture, cell fate diversification, cardiovascular system, cardiac conduction system, central nervous system, haemodynamics, growth factor signaling.

Summary:
The establishment of extremely complicated structures and functions of our organ systems depends upon orchestrated differentiation and integration of multiple cell types. Our group focuses to explore a common developmental plan for successful organogenesis, by investigating the mechanisms involved in the differentiation and patterning of the cardiovascular and central nervous systems.

David Pearce, B.A., M.D.
Professor of Medicine

Research Interests:
Epithelial biology as it relates to cardiovasculare function: hypertension, fluid and electrolyte regulation.

Summary:

Kevan M Shokat, Ph.D.
Professor and Chair

Research Interests:
DESIGN OF DRUGS TO TREAT CARDIOVASCULAR DISEASE, CANCER, AND AUTOIMMUNE DISEASES.

Summary:

Biao Wang, Ph.D.
Assistant Professor

Research Interests:
Obesity, diabetes, hormones, cAMP, kinase, signaling transduction, transcriptional regulation

Summary:
Type II diabetes mellitus accounts for 90-95% of all cases of diabetes, and this heterogeneous disorder afflicts an estimated 6% of the adult population in Western society. Energy imbalance by high calorie intake and/or lack of physical activity can lead to obesity, which is often associated with an increased risk of developing insulin resistance followed by type II diabetes. Our research is focused on understanding how circulating hormones modulate energy balance in multiple metabolic tissues, and how disruption of these hormonal actions contributes to pathophysiology of type II diabetes.

Ethan J Weiss, M.D.
Associate Professor

Research Interests:
Coagulation, thrombosis, hemostasis, fibrinolysis, genetics, platelet, sexual dimorphism, growth hormone signaling, fatty liver disease, regulation of energy metabolism and obesity

Summary:
Our group has two main interests. The first is to understand the mechanisms underlying the regulation of energy metabolism by growth hormone. Growth hormone is well-known to promote lipolysis as a means of mobilizing energy from stores in the form of free fatty acids. To accommodate tissues and organs with increased energy needs, fatty acid uptake is also regulated by growth hormone. The precise molecular mechanisms driving these two processes remain unclear. With an aim toward understanding mechanisms of obesity and related conditions, we use a molecular and cellular approach combined with mouse genetic models to understand how growth hormone regulates lipolysis and the uptake of fatty acid by cells and tissues.

Our second interest is in defining novel mechanisms of thrombosis susceptibility. Our group has had a long interest in thrombosis. Recently, we have focused on understanding ways to modulate thrombosis risk without increasing the risk of bleeding. Here, we also use molecular, cellular, and mouse genetics approaches.

Allison Wanting Xu, M.Sc., Ph.D.
Associate Professor

Research Interests:
Hypothalamic regulation of energy balance, obesity and type 2 diabetes

Summary:
Our lab's major research focus is to understand the mechanisms by which energy balance is regulated. We use a combination of mouse genetics, whole body physiology and real time imaging approaches to elucidate the function of specific hypothalamic neurons and how they integrate peripheral metabolic signals under distinct physiologic conditions.

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