Terminally differentiated ventricular muscle cells virtually cease to proliferate, and subsequent cardiac growth occurs almost exclusively by cell enlargement. Hence, failure to increase cell number preludes cardiac regeneration as a means to reconstitute functional mass after infarction or other insult. This irreversible growth arrest poses a therapeutic challenge, especially in the elderly, where the includes of infarction and heart failure is high. Using an array of recombinant viruses to direct the expression of adenoviral EIA proteins, the applicant has recently demonstrated evidence for dual pocket protein-and p300-dependent pathways that govern the cell cycle in cardiac muscle. Drawing on these developments the present application proposes to study in depth the endogenous occupant of the """"""""pocket"""""""", the transcription factor known as E2F; modulators of pocket protein function in the heart, known as cyclins and clyclin-dependent protein kinases (Cdks); and the molecular relationship between the pocket protein-and p300-dependent mechanisms.
Specific Aims of the present project are: (1) to establish molecular mechanisms for the phenotype effects of E2F ( activation of the cell cycle, and repression of tissue-specific genes) in cardiac muscle cells; (2) to clarify what role is played by endogenous regulators of free E2F (G1 cyclins, Cdks, and Cdk inhibitors) in cardiac muscle cells; (3) To determine the epistatic relationship between E2F and the p300 pathway in cardiac muscle cells; and (4) To investigate the function of E2F in adult cardiac muscle in vivo, by direct injection of e2F virus and by cardiac-restricted homologous recombination of the pocket protein gene, Rb.
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