Project: Research project

Project Details


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.
Effective start/end date1/1/9912/31/03


  • National Institutes of Health: $298,000.00
  • National Institutes of Health: $299,000.00
  • National Institutes of Health: $298,000.00
  • National Institutes of Health: $298,000.00
  • National Institutes of Health: $298,500.00


  • Medicine(all)


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