CLONING OF A POTENTIAL REGULATOR OF THE DHAND FACTOR

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION (Adapted from applicant's description): Characterizing the molecular signaling cascade that directs cardiac ventricular maturation is vital to our understanding of normal cardiac development and may enable identification of the causes of congenital cardiac defects that affect ventricular structure or function. Abnormalities of ventricular development are associated with very high morbidity and mortality throughout the pre- and postnatal period. The goal of this laboratory is to characterize elements of the signaling cascade that direct right and left ventricular development by examining the function and regulation of the dHAND and eHAND basic helix-loop- helix (bHLH) transcription factors. These two factors appear to be vital elements in distinct regulatory pathways that direct right (dHAND) and left (eHAND) ventricular development. During preliminary studies in our laboratory, a novel kinase was identified that interacted with dHAND in a yeast two hybrid model. This kinase was strongly expressed in the developing and mature heart with limited expression in skeletal muscle. It has been localized to a region that is linked to an inherited developmental abnormality of ventricular structure and electrophysiologic function, arrhythmogenic right ventricular dysplasia (ARVD). This study will be a pilot project to characterize this novel gene, determine if it has a potential regulatory role in dHAND and/or eHAND function, and define its genomic structure in preparation for its evaluation as the gene responsible for one form of ARVD.