Clinical recovery from myocardial infarction is thwarted, in part, by inability of surviving ventricular myocytes to reconstitute functional cardiac mass through a corresponding, compensatory increase in cell number. This highlights the limited capacity to restore cardiac mass by hypertrophy alone, and deleterious effects associated with hypertrophy that further impair survival. On-going myocyte loss also appears likely as an eventual contributor to end-stage heart failure. Conventional therapies for heart failure are aimed at rescuing jeopardized myocardium, optimizing mechanical load, or augmenting the mechanical performance of surviving myocytes. In principle, strategies to increase the number of functional ventricular myocytes have potential for a clinical benefit. (This theme is among the highest priorities expressed by the NHLBI Special Emphasis Panel on Heart Failure Research and the present RFA.) Three complementary, gene-based approaches have been brought to bear on the problem of cardiac cell number in this Collaborative RO1-transdifferentiation, manipulation of cell cycle constraints, and interference with pathways for programmed cell death (apoptosis). Viral delivery of cardiogenic transcription factors and upstream cardiogenic signals will be explored by Dr. Robert Schwartz. Drs. Michael Schneider and Loren Field will use gain-and loss-of- function mutations to dissect the """"""""post-mitotic"""""""" phenotype in vivo, and will use co-precipitation or interaction cloning to isolate the endogenous cardiac proteins affecting cell cycle exit. Dr. Konstantin Galaktionov, an expert on Cdc25, will study molecular regulators of the G2/M transition, a second checkpoint that must be overcome for cell number to be increased. Mechanisms and countermeasures for cardiac apoptosis will be tested by Dr. Doug Mann, with emphasis on dilated cardiomyopathy triggered by overexpression of tumor necrosis factor alpha, and on investigations of human myocardium.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061631-04
Application #
6490629
Study Section
Special Emphasis Panel (ZHL1-CSR-F (S1))
Program Officer
Reinlib, Leslie
Project Start
1999-01-01
Project End
2003-12-31
Budget Start
2002-01-01
Budget End
2002-12-31
Support Year
4
Fiscal Year
2002
Total Cost
$298,000
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202