"The Role of HDAC3 in Cardiac Growth and Development"

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DESCRIPTION (provided by applicant): The process of cardiac development incorporates cell differentiation and proliferation, which lead to the formation of the mature heart. Abnormalities in cardiac development result in congenital heart diseases, which is the most frequent form of birth defects in humans. More specifically, disruption of pathways affecting cardiac growth could be the underlying etiology in a subset of children born with hypoplastic left or right heart. Understanding the myocardial-specific molecular mechanisms by which signaling pathways control proliferation during cardiogenesis is a central issue in cardiac development and disease. These pathways are complex, and in many cases implicate transcription factors and cell cycle regulators. Covalent chromatin modifications play a critical role in transcriptional regulation and cell cycle progression, and therefore are expected to affect theses processes in the heart as well. Of these modifications, acetylation by histone acetyltransferases (HATs) and its reversal by histone deacetylases (HDACs) have been most studied and appreciated as a key event in regulating these processes. Experimental data from the mouse and zebrafish models suggest that HDAC1, a class I HDAC family member, plays an important role in embryonic cardiac growth and development. However, the role of other class I HDACs in cardiac growth and development remains unknown. As an extension of the principal investigator's interest in embryonic myocardial growth and development, he initiated a comprehensive analysis of the role of class I HDACs other than HDAC1. Preliminary studies suggest an important role for HDAC3, a class I member, both in cardiac growth and in development. In this pilot study, the investigators propose experiments that will offer insights into the role of HDAC3 in embryonic cardiac growth and development. They will pursue two aims: Specific Aim 1 will determine the effect of hdac3 deficiency in the zebrafish embryonic heart. The investigators will address this question by generating hdac3-deficient zebrafish embryos by disrupting hdac3 function with morpholino antisense oligonucleotides and comparing them with hdac3 mutants. The hdac3 deficient embryos will be evaluated by morphological and functional analysis with particular emphasis on the heart. Heart characterization will be completed by assessment of differentiation by the use of molecular markers, cell count determination, apoptosis, and proliferation assays. Specific Aim 2 will determine what are the cardiac defects in the hdac3 deficient embryos due to the loss of hdac3 function within cardiomyocytes or due to effects upon cellular functions in other support tissues? The investigators will address this question by reciprocal cell transplantations between control and hdac3-deficient embryos. They will also use selected molecular markers to dissect extracardiac processes relevant to cardiac development that are potentially affected in the hdac3 deficient embryos.