Cardiovascular diseases are the leading cause of death in developed countries, with a very poor prognosis for patients in advanced stages. Congestive heart failure, the end result of many cardiovascular problems is one of the most expensive health problems in the United States. Although there have been dramatic improvements in the treatment of cardiovascular diseases their continued poor prognosis makes the development of novel therapies necessary. During cardiac development, during normal life and during cardiovascular disease there are complex changes in gene expression controlled by multiple transcription factors and their cofactors (Nkx2, MEF2, NFAT, SRF, GATA, HDACs, HATs and TEF-1). It is known how the activity of some but not all of these factors, such as TEF-1 is regulated at a gross level. The research in this proposal will concentrate on determining the role of the TEF-1 gene family in transcriptional regulation in the heart. The studies will use rat neonatal cardiac myocytes, a well established in vitro model system of normal and diseased heart. The research in this grant will address the hypothesis that interactions between MCAT sites, TEF-1 proteins, their cofactors, and other cardiac transcription factors are key in generating the complex patterns of gene expression in normal and hypertrophic cardiac myocytes. The experiments will (1) determine if TEF-1 regulates endogenous cardiac gene expression in normal and hypertrophic cardiac myocytes (dominant negative proteins, siRNA), (2) determine if MCAT core sequence affects the activity of MCAT sites by influencing the interaction of TEF-1 with its cofactors, (3) isolate novel TEF-1 cofactors by state of the art MS/MS, and (4) study how the TEF-1 cofactors (YAP65, TAZ, CK2) and TEF-1 interact with each other and with other cardiac transcription factors to regulate gene expression in cardiac myocytes under normal and hypertrophic conditions. The approaches that will be used include expression of dominant negative TEF-1 proteins using adenoviral vectors. These analyses will detail the mechanisms of promoter response to specific signals in normal and diseased cardiac myocytes, leading to improved treatments for heart disease.
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