The objective during the award period is to develop the candidate's knowledge and investigative skills in membrane biology and cellular electrophysiology. The subject for study will be the coronary artery smooth muscle cell whose contractile and proliferative responses to numerous humoral and therapeutic agents have given it a pivotal role in vascular and myocardial pathophysiology. Under the sponsorship of Dr. Thomas W. Smith and the preceptorship of Dr. David E. Clapham, the candidate will focus his experimental program on the isolated cell preparation of bovine coronary artery smooth muscle and the electrophysiology of its calcium channels, which are known to mediate such important responses as muscle contraction and exocytosis. In Phase I, cell isolation procedures will be refined in order to produce optimal cells expressing native physiology. The patch clamp technique of Neher and Sakmann will be used to characterize the basal behavior of the calcium channel(s) by their voltage-dependence, kinetics, and their response to transmitters and antagonists as measured in whole-cell and single-channel recordings. In addition, during Phase I, formal coursework in cell and membrane biology and electrophysiology at Harvard Medical School will broaden and strengthen the candidate's working knowledge of his investigations. In Phase II, the modulation of calcium channel behavior by transmitters, hormones, growth factors and therapeutic agents will be studied by means of controlled perfusion of the intracellular and extracellular membrane surfaces with the agent under study. In addition, the effects of intracellular agents, such as modifiers and components of the adenylate cyclase and phosphatidyl inositol second messenger pathways, on calcium channel activity will be studied. Through a coherent program of intensive research and coordinated didactic learning, the award would allow the candidate to gain the knowledge and experience to become an independent, productive investigator in the membrane biology and cellular electrophysiology of cardiovascular science.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Physician Scientist Award (K11)
Project #
5K11HL001957-03
Application #
3087449
Study Section
Research Manpower Review Committee (MR)
Project Start
1987-05-01
Project End
1992-04-30
Budget Start
1989-05-01
Budget End
1990-04-30
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Treasure, C B; Vita, J A; Ganz, P et al. (1992) Loss of the coronary microvascular response to acetylcholine in cardiac transplant patients. Circulation 86:1156-64
Bittl, J A; Yeung, A C; Vekshtein, V et al. (1992) Estimation of mitral valve area from regression analysis of the pressure gradient in mitral stenosis. Am J Cardiol 69:1050-5
Treasure, C B; Vita, J A; Cox, D A et al. (1990) Endothelium-dependent dilation of the coronary microvasculature is impaired in dilated cardiomyopathy. Circulation 81:772-9
Gordon, J B; Ganz, P; Nabel, E G et al. (1989) Atherosclerosis influences the vasomotor response of epicardial coronary arteries to exercise. J Clin Invest 83:1946-52
Vita, J A; Treasure, C B; Ganz, P et al. (1989) Control of shear stress in the epicardial coronary arteries of humans: impairment by atherosclerosis. J Am Coll Cardiol 14:1193-9
Fish, R D; Sperti, G; Colucci, W S et al. (1988) Phorbol ester increases the dihydropyridine-sensitive calcium conductance in a vascular smooth muscle cell line. Circ Res 62:1049-54