The candidate, Dr. Steven Fisher, recently completed his medical subspecialty training in a four year cardiology fellowship at the University of Vermont. During that time he trained for over two years molecular biology laboratory studying cardiac hypertrophy arid the regulation of gene expression. The purpose of the proposed clinical investigator award is to provide advanced training to facilitate the applicant's study of vascular smooth muscle cells in normal and diseased states. The hypothesis to tested is that hypertrophy of smooth muscle cells is associated with alterations of gene expression, particularly in the myosin light chain kinase (MLCK) gene. This alteration is implicated in explaining intractile abnormalities of smooth muscle cells which occur in hypertensive diseases. As his sponsor, Dr. Mitsuo Ikebe provides years of experience in the examination of the molecular and biochemical assist of smooth muscle contraction arid relaxation. The proposed project consists of the following: 1) to relate the level of expression of MLCK protein and mRNA to the kinase activity in various tissues 2 to determine how the expression and activity is affected by vascular smooth muscle hypertrophy 3) to clone the gene and study its transcriptional control. Dr. Toni Scarpa, as chairman of the Dept. of Physiology and Biophysics, and Dr. Marc Thames, is chief of the Division of Cardiology, will form an advisory committee and meet with the applicant quarter-annually. Case Western Reserve University School of Medicine provides a rich resource for didactics, including weekly seminars (Physiology) in muscle mechanics and weekly (Cardiology) grand rounds, in which the applicant will participate. This program is designed to mold Dr. Fisher into productive physician scientist who utilizes basic cell and molecular techniques to study clinically relevant smooth muscle disease processes.
| Dirksen, Wessel P; Mohamed, Sotohy A; Fisher, Steven A (2003) Splicing of a myosin phosphatase targeting subunit 1 alternative exon is regulated by intronic cis-elements and a novel bipartite exonic enhancer/silencer element. J Biol Chem 278:9722-32 |
| Khatri, J J; Joyce, K M; Brozovich, F V et al. (2001) Role of myosin phosphatase isoforms in cGMP-mediated smooth muscle relaxation. J Biol Chem 276:37250-7 |
| Dirksen, W P; Vladic, F; Fisher, S A (2000) A myosin phosphatase targeting subunit isoform transition defines a smooth muscle developmental phenotypic switch. Am J Physiol Cell Physiol 278:C589-600 |
| Fisher, S A; Siwik, E; Branellec, D et al. (1997) Forced expression of the homeodomain protein Gax inhibits cardiomyocyte proliferation and perturbs heart morphogenesis. Development 124:4405-13 |
