Areas of Research Focus
The primary mission of the Division is to undertake research that advances our understanding of mechanisms of drug action in humans in order to improve therapeutics. There are six major areas of research focus within the division.
- Pharmacogenetics and drug disposition and metabolism.
- Fatty acid oxidation and lipid mediator pharmacology.
- Ion channel pharmacology and arrhythmia pharmacogenomics.
- Human cardiovascular pharmacology and autonomic dysfunction.
- Bone and cancer pharmacology.
All of these areas are vibrant with multiple junior and senior faculty members engaged in these endeavors.
Pharmacogenetics and Drug Disposition and Metabolism in Humans
Senior Investigators: Mike Stein, Dan Roden, Jens Titze and Nancy Brown. The focus of this area of research is to understand basic mechanisms of drug disposition and metabolism in humans. Historically, this has been a major research interest of the division and work emanating from it has led to such important concepts as first pass drug metabolism, that cytochrome P450's are a major contributor to phase I drug metabolism, and that interindividuality in drug metabolism in humans contributes to differences in drug efficacy and safety. Research in this component of the division continues to contribute importantly to our understanding of drug disposition and metabolism. Drs. Stein, Roden, and Brown are actively engaged in (A) defining the genetic basis of drug variability using pharmacogenomic approaches, and (B) moving our rapidly expanding knowledge about these variants into routine clinical practice. Dr. Titze is interested in the association between interstitial and cellular Na+ storage, hypertension, and cardiovascular disease and how therapeutic or dietary manipulation may prevent Na+ storage.
Fatty Acid Oxidation and Lipid Mediator Pharmacology
Senior Investigators: John Oates, Alan Brash, Jack Roberts, Claus Schneider. Research in this area centers around the role of oxidized bioactive lipid mediators in human health and disease. Arachidonic acid and related polyunsaturated fatty acids are important components of cellular membranes. They can be oxidized enzymatically and non-ezymatically to a variety of different eicosanoids termed either prostaglandins, leukotrienes, or isoprostanes. These compounds exert potent biological activities that mediate a number of important human physiological and pathophysiological processes ranging from atherosclerosis to cancer to neurodegenerative disorders. A major focus of investigators in the division is gaining a better understanding of how formation and metabolism of eicosanoids causes human diseases. For example, Jack Roberts determined that excessive isoprostane formation occurs in many human disorders and that these compounds mimic enzymatically-derived lipid mediators such as prostaglandins in that they exert biological effects by interacting with prostaglandin receptors. On the other hand, Alan Brash and Claus Schneider are actively engaged in research examining fundamental mechanisms of prostaglandin and leukotriene formation and determining how these proteins function catalytically. John Oates and Jack Roberts have a particular interest in neurodegeneration and are exploring how highly reactive products of lipid peroxidation that contain carbonyl moieties and are termed isoketals adduct important proteins resulting in disease.
Ion Channel Pharmacology and Arrhythmia Pharmacogenomics
Senior Investigators: Dan Roden, Bjorn Knollman, Kathy Murray. Beginning in the 1970's, research in this component of the division focused on basic mechanisms of anti-arrhythmic drug action. Over the years, a variety of fundamental advances have been made with respect to understanding the clinical pharmacology of these agents. For example, the observation that the administration of certain drugs to prevent ventricular arrhythmias actually leads to an increase in cardiovascular mortality was performed by Dan Roden and colleagues and led to a fundamental shift in the thinking that not all anti-arrhythmic therapy is beneficial. More recently, a better understanding of the structure, function, and signaling mechanisms of sodium, potassium, and calcium channels that contribute to the normal human heart beat has been a focus of work by Drs. Murray and Roden. Dr. Knollman is exploring the role of calcium signaling in the pathogenesis of cardiac arrythmias. A major thrust of research in this component of the division is also related to a determination of the genetic components of the human response to antiarrhythmic agents. Dr. Roden and colleagues are members of the Pharmacogenomics Network, an NIH funded network, and are actively engaged in research examining the genetic basis for the interindividual variability in anti-arrhythmic drug response.
Human Cardiovascular Pharmacology and Neural Dysfunction
Senior Investigators: David Robertson, Mike Stein, Italo Biaggioni, Andre Diedrich, Nancy Brown and David Harrision. This is a broad-based component of the division that spans several important areas of research related to human cardiovascular function. Nancy Brown has a particular interest in the rennin-angiotensin-aldosterone system and how therapeutic manipulation of this axis results in the prevention or amelioration of common cardiovascular diseases such as hypertension and heart failure. To undertake her work, she utilized a variety of biochemical and genetic approaches. Dr. Stein is interested in factors related to normal and abnormal vascular function in diseases ranging from systemic lupus erythematosus to atherosclerosis. An important component of their research utilizes pharmacogenetics. Dr. Harrison's research is on inflammation and immunity which are believed to be intimately related to oxidative injury. His research has shown that the central nervous system plays an essential role in T cell activatin in hypertension and vascular dysfunction.
The second component of this arm of the division studies the role of the autonomic nervous system in human physiology and pathophysiology. Drs. Robertson, Biaggioni, and Diedrich have applied basic pharmacologic approaches to understanding human disorders of autonomic dysfunction. Their work has defined a fundamental role for deficiencies in various dopaminergic metabolizing enzymes in these diseases and has elucidated the role of adenosine as a modulator of vascular tone.
Bone and Cancer Pharmacology
Senior Investigators: Xiangli Yang, Florent Elefteriou. This is the newest area of research in the Division with the recruitment of the late Greg Mundy and colleagues to Vanderbilt in 2006. The major thrust of research by investigators in this component of the Division involves cellular interactions of the bone microenvironment in human health and disease with a focus on understanding mechanisms responsible for disease manifestations in the skeleton and the use of this knowledge for rational drug discovery. Investigators study the role of hormones, cytokines, growth factors and transcription factors on bone cell differentiation and function as well as on tumor cells that have been metastasized to bone. Their work is of direct translational relevance and has led to important discoveries related to modulation of bone formation.
Senior Investigators: Mike Stein, Kathy Murray. Members of Clinical Pharmacology work closely with Dr. Wayne Ray and others in the Division of Pharmacoepidemiology to study the effects of drugs in large populations. This work has focused on the cardiovascular and gastrointestinal adverse effects of anti-inflammatory drugs, and the cardiovascular toxicity of antibiotics and psychotropic medications. The studies are performed as part of the mission of the Vanderbilt CERT (Centers for Education and Research on Therapeutics) a research program administered by the Agency for Healthcare Research and Quality (AHRQ).