This project is aimed at defining the functional deficits resulting from cardiac myosin mutations that cause hypertrophic cardiomyopathy (HCM). Experiments will be carried out on human slow skeletal muscle fibers obtained from biopsies from normal and HCM patients, as well as on cultured quail myotubes transfected with human cardiac myosin heavy chains. The central hypothesis is that the mutant myosin in HCM has impaired function. Dr. Lankford will use molecular techniques to create mutant human myosin heavy chain constructs that will be expressed in quail myogenic cell cultures. Some of the mutant myosins to be constructed will resemble the naturally occurring mutant myosins found in patients with HCM, while others will have different mutations. Mechanical studies will be performed on isolated myotubes from these cultures to allow quantification of the performance of mutated myosin. The applicant will also study skeletal muscle biopsies from humans with HCM. These studies in these two different systems will allow an increased understanding of the process of force generation by actin- myosin interaction, and the structure/function relationship in the myosin heavy chain. The studies will be performed in the laboratory of Dr. Lee Sweeney, an assistant professor, with consultation with Dr. Judith L. Swain, an internationally recognized leader in the field of muscle biology.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL003172-04
Application #
2702076
Study Section
Research Training Review Committee (RTR)
Project Start
1995-05-15
Project End
2000-04-30
Budget Start
1998-05-28
Budget End
1999-04-30
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Loh, E; Lankford, E B; Polidori, D J et al. (1999) Cardiovascular effects of inhaled nitric oxide in a canine model of cardiomyopathy. Ann Thorac Surg 67:1380-5
Vemuri, R; Lankford, E B; Poetter, K et al. (1999) The stretch-activation response may be critical to the proper functioning of the mammalian heart. Proc Natl Acad Sci U S A 96:1048-53
Lankford, E B; Korzick, D H; Palmer, B M et al. (1998) Endurance exercise alters the contractile responsiveness of rat heart to extracellular Na+ and Ca2+. Med Sci Sports Exerc 30:1502-9