The Division of Clinical Pharmacology aims to undertake research that advances our understanding of mechanisms of drug action in humans in order to improve therapeutics.
The division has traditionally pursued translational research, and is well poised to contribute to achieving several goals of the Vanderbilt Research Enterprise Strategic Plan, including those related to personalized health and healthcare, and therapeutic discovery and translation.
In this mission, the division collaborates with several internal and external research centers, labs and institutes, including the Oates Institute, Vanderbilt Center for Bone Biology, Vanderbilt Center in Molecular Toxicology and the Vanderbilt Institute of Chemical Biology, as well as many individual investigators throughout Vanderbilt.
Early-career and senior faculty are engaged in six major areas of research within the division. These include:
Senior Investigators: Drs. Dan Roden, Mike Stein and Jonathan Mosley
The focus of this area of research is to use genetic approaches to understand variability in human drug response. Historically, drug metabolism and disposition has been a major research interest of the division, and work emanating from it has led to several important concepts such as first pass drug metabolism, that cytochrome P450s are a major contributor to phase I drug metabolism, and that interindividual variability in drug metabolism in humans contributes to differences in drug efficacy and safety. Researchers in this component of the division continue to advance the field of pharmacogenetics and provide a better understanding of the clinical importance of genetic variability affecting drug disposition and metabolism. They also use genetic methods, particularly as applied to electronic health records, to better recognize individuals at risk for drug toxicity, find new drug targets, predict unexpected adverse effects of drugs, and identify new biology driving responses to drugs. Researchers collaborate widely inside and outside Vanderbilt using many sources of data (e.g., BioVU, eMERGE, All of Us, UK Biobank) and have broad areas of interest including arrythmia, anticoagulants, lipids, coronary heart disease, autoimmune disease and sepsis.
Senior Investigators: Drs. Dan Roden, Bjorn Knollmann, Kathy Murray, Andrew Glazer and Brett Kroncke
Research in this component of the division has focused on basic mechanisms of antiarrhythmic drug action and variability in response to antiarrhythmic drugs since the 1970s. Investigators were among the first worldwide to define key pharmacogenetics factors outcomes during treatment with antiarrhythmics and many other drugs. The Vanderbilt Arrythmia Service, now one of the most prominent in the nation, started in the division, and investigators were participants in key clinical trials that defined efficacy and toxicity of antiarrhythmic drugs. One example was the Cardiac Arrhythmia Suppression Trial (CAST) that defined proarrhythmic effects of sodium channel block. The Roden Lab continues to focus on mechanisms underlying such proarrhythmia, and is collaborating with the Glazer and Kroncke research groups on methods to establish function of thousands of variants in key ion channel and other genes controlling cardiac arrhythmogenesis. Mechanisms underlying susceptibility to the common arrhythmia atrial fibrillation drives cellular and mouse studies in the Murray Lab. Dr. Knollmann is internationally recognized for his expertise in understanding control of intracellular calcium and how this affects arrhythmia susceptibility. He also directs the Vanderbilt Center for Arrhythmia Research and Therapeutics that includes approximately 40 investigators who work on arrhythmia mechanisms, susceptibility and optimal treatment, from patients referred for management (e.g., refractory arrhythmias or genetic arrhythmia syndromes) to animal and cellular models, including a current major focus on the use of induced pluripotent stem cells.
Senior Investigators: Drs. Matt Alexander, Annet Kirabo, David Harrison, David Patrick and Monica Santisteban
Investigators in Clinical Pharmacology have led the field in defining how inflammation and immune activation participate in cardiovascular diseases and the end-organ damage associated with diseases like hypertension and metabolic dysregulation. A major contribution has been an investigation of the role of lipid peroxidation, and ultimately post-translational modification of self-proteins by peroxidized lipid products in inflammation. One such product family are the isolevuglandins, which rapidly ligate with lysines on self-proteins. Peptides from these are presented in major histocompatibility complexes and activate T cells and innate lymphoid cells. Dr. Kirabo is investigating how salt activates this pathway in experimental models and humans, and has shown a role of the microbiome in forming these. Dr. Alexander has used non-biased single cell phenotyping to identify unique populations of regulatory T cells that are altered in human and murine hypertension. Dr. Patrick has established a role of isoLG-adducts in systemic lupus erythematosus (SLE), and is interested in how these alter neutrophil activation and the role of neutrophil extracellular traps in hypertension and SLE. Dr. Santisteban is defining how hypertension is associated with cognitive decline, and the role of inflammatory cells in this process.
Senior Investigators: Drs. Italo Biaggioni, Cyndya Shibao, Andre Diedrich and Luis Okamoto
The Vanderbilt Autonomic Function center has a robust research program that focuses on mechanistic studies in humans using pharmacological probes to dissect the interactions between neural (autonomic), metabolic (renin-angiotensin, insulin) and local (adenosine, nitric oxide, incretins) involved in cardiovascular regulation, and to understand how these interactions participate in the pathophysiology of hypertension and associated neurological and metabolic disorders in humans.
By blocking autonomic ganglia neurotransmission and baroreflex buffering, we have shown that endogenous nitric oxide normally restrains blood pressure by about 30 mmHg, and that nitric oxide excess contributes to the orthostatic hypotension of autonomic failure. We have also found that hypertension and endothelial dysfunction can be reversed, and insulin resistance can be improved by autonomic blockade.
Our research in autonomic dysfunction has resulted in the discovery of four novel genetic autonomic disorders, including dopamine-beta-hydroxylase deficiency, CYB561 deficiency, norepinephrine reuptake deficiency, and familial autonomic ganglionopathy. The finding that the norepinephrine precursor droxidopa reverses the norepinephrine deficiency of dopamine-beta-hydroxylase deficiency ultimately led to its development for the treatment of orthostatic hypotension, only the second FDA-approved drug for this purpose. We are also repurposing the norepinephrine reuptake atomoxetine for the treatment of orthostatic hypotension and acarbose for postprandial hypotension.
Autonomic abnormalities are prominent in patients with the long COVID syndrome and in patients with Postural Tachycardia Syndrome. We are exploring strategies to lower sympathetic activation and enhancing vagal function with vagal nerve stimulation in the treatment of these patients.
Senior Investigators: Drs. Jeff Nyman, Sun Peck, Rachelle Johnson, Elizabeth Rendina Ruedy, Julie Rhoades Sterling and Ella Knapik
Research investigators at the Vanderbilt Center for Bone Biology (VCBB) investigate diseases of bone and mineral metabolism. Ongoing projects aim to identify mechanisms regulating bone remodeling and repair, cancer-induced bone disease, osteomyelitis, fracture repair and embryonic bone development. By investigating the diseases and conditions that negatively affect bone, cartilage, and muscle and their ability to heal and regenerate, the VCBB goals are to develop new treatment strategies and diagnostic tools. In doing so, research may improve the quality of life for patients with compromised bone, articular cartilage, and muscle due to aging, trauma, infection and disease. Access to multiple core resources and equipment at VUMC and Vanderbilt University allows us to perform molecular, cellular and biochemical studies, and to precisely quantify changes in bone volume, architecture, biomechanical properties and histomorphometric parameters upon gene alterations, growth, aging, disease, trauma, or pharmacologic treatments. The VCBB is a cross-disciplinary center, with members of Orthopedic Surgery (Stephanie N. Moore-Lotridge, Jonathan Schoenecker), Endocrinology (Kathrin Dehir), Rheumatology (Bobo Tanner and Leslie Crofford), Biomedical Engineering (Jonathan Brunger, Scott Gulcher and Craig Duvall), Pediatrics (Jim Cassat, Jonathan Schoenecker and Jill Simons), and Chemical Engineering (Marjin Rafat) as active participants. Students from multiple departments, including Pathology, Microbiology and Immunology, Medicine, Cancer Biology, Pharmacology, Biochemistry and Engineering are also actively involved in this research activity. Feel free to contact the project leaders if you have questions about projects and if you have interests in joining our group.
Senior Investigators: Mike Stein and Kathy Murray
Members of Clinical Pharmacology work closely with Dr. Wayne Ray and others in the Department of Health Policy to study the effects of drugs in large populations using databases such as Medicaid and Medicare. This work has focused on the cardiovascular and gastrointestinal adverse effects of anti-inflammatory drugs; the cardiovascular toxicity of a range of medications including antibiotics, psychotropics and opioids; the adverse consequences of drug-drug interactions mediated by cytochrome P450 enzymes and the P-glycoprotein efflux transporter; and the efficacy and safety of direct-acting oral anticoagulants.