This investigative team has been interested in improving the current understanding of the influence of age on the heart. They have observed that the myocardial response to hemodynamic stress in terms of ventricular hypertrophy, protein synthesis and RNA synthesis was decreased in the old compared to young adult mammalian hearts. they found that there were both qualitative as well as quantitative differences in the pattern of gene expression, including an age-associated decrease in the induction of immediate early genes (e.g. c-fos) following stress. To characterize transcription factor binding activity in the heart during aging, they studied the c-fos promoter, and found that the basal binding activities of E2F and AP1 proteins were reduced with age, while CREB and SP1 binding activities were unchanged. However, they found that the basal SRE binding activity in the hea about was increased w aboute. Consistent with this we found that in old rat hearts there was also increased expression of SRF, transcription factor that is the major SRE binding factor. This increased SRF protein in aged hearts was hyperphosphorylated, and appeared to be localized much more in the cytoplasm in the hearts of the old vs. that of the young adult animals. Although it would also be of interest to pursue the role and mechanism of decreased AP1 and E2F binding in cardiac function, they have chosen to initially concentrate on understanding the mechanism and consequence of increased SRF/SRE binding because of its central role in regulating myogenic gene expression. SRF is an important transcription factor that has been shown to be a central regulator of many muscle specific genes, including cardiac and skeletal actin, dystrophin, myosin light chain, and atrial natriuretic peptide. SRF is also an important regulator of many primary response genes, such as c-fos, that are implicated in cell growth and differentiation. Based on the fact that SRF is a key regulator of many cardiac-specific genes, and their observation that SRF protein expression is increased in aging hearts, they propose the working hypothesis that altered transcription regulation of SRF expression can lead to pathogenic changes in the heart that resemble those seen in aged hearts.
Specific aims are: (1) to investigate the effect of increased SRF expression on the heart; (2) to determine the effect of increased SRF protein in the cell; and (3) to characterize the myocardial program of gene expression associated with increased SRF.
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