) The long term goal of the proposed studies is to understand the structure/function relationships of the two major isoforms of the myosin heavy chain (MyHC). The MYHC is the largest protein in the cardiac sarcomere and, in vertebrates, exists predominantly in two isoforms, V1 and V3, encoded by a-MyHC and B-MYHC, respectively. The two isoforms have different expression patterns based on species, developmental stage, and disease, additionally, they have different intrinsic ATPase activities. In humans, mutations in the more abundant B-MyHC isoform have been linked to familial hypertrophic cardiomyopathy. Most of the known mutations are clustered in the globular head of the protein, which contains the sites of actin and essential light chain binding, the site of ATPase activity, and the region connecting two reactive cysteines. In order to define the role of isoform specificity, transgenic and targeted (""""""""knockout"""""""") mice will be used for the following Specific Aims: (1) Overexpression of the mouse B-MyHC isoform (V3) on the wild type a-MyHC+/+ (V1) background to generate mice with varying V1/V3 ratios, and (2) Complete replacement of the V1 isoform with V3 by expressing the B-MyHC isoform on the a-MyHC null (""""""""knockout"""""""") background. Thorough analysis of these animals from the molecular to whole organ level will highlight the role of isoform specific ATPase activity in modulating the complex protein interactions of the cardiac sarcomere which underlie cardiac function.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL003769-02
Application #
2857554
Study Section
Special Emphasis Panel (ZHL1-CSR-Y (O1))
Project Start
1998-01-01
Project End
2002-12-31
Budget Start
1999-01-01
Budget End
1999-12-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229