Cardiomyocytes in the adult mammal exhibit little if any capacity to undergo cell division. Consequently cardiomyocyte loss due to injury or disease is irreversible. Identification of the gene products which regulate cardiomyocyte proliferation and terminal differentiation might provide molecular targets with which to induce therapeutic myocardial growth in the adult heart. We have previously generated a series T-Ag associated proteins in transgenic mice which heritably develop myocardial tumors. In this competitive renewal application, we will examine the roles of four of these proteins in normal and pathologic cardiomyocyte growth, and will specifically test the hypothesis that they play a critical role in cardiomyocyte terminal differentiation by generating transgenic mice in which they are either over-expressed or absent during myocardial development.
Four Specific Aims are proposed:
Specific Aim #1 will test the hypothesis that p380 imparts a regulatory role during myocardial development by examining it's expression during normal and pathologic growth, and by generating transgenic animals which abnormally express the protein.
Specific Aim #2 will asses the role of p193 in myocardial development using approaches paralleling those employed in Specific Aim 1 for the analysis of p380.
Specific Aim #3 will generate transgenic mice which constitutively express p107 (wild-type and site-directed mutants) and assess any effects on cardiomyocyte terminal differentiation and/or hypertrophic myocardial growth. P107 is a T-Ag associated protein with significant homology to the retinoblastoma gene product, and aside form p53 is the most abundant T-Ag associated protein in our transgenic cardiomyocyte preparations.
Specific Aim #4 will examine the role of the pTSC2 tumor suppressor in myocardial development by generating transgenic mice which lack the gene. Mutations at the pTSC2 locus gives rise to tuberous sclerosis, a familial cancer in which 50% of TS patients develop myocardial tumors comprised of differentiated, proliferating cardiomyocytes. We hypothesize that these proteins participate in the regulation of cardiomyocyte proliferation and/or terminal differentiation, ad further that T-Ag blocks the normal activity of the associated proteins in transformed cardiomyocytes. This competitive renewal application will specifically test these hypotheses. If the putative regulatory roles for these proteins are confirmed, they may serve as intracellular targets for therapeutic myocardial growth in the adult heart.
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