The objective of this Mentored Minority Faculty Development (K01) Award is to develop Dr. Cathy Hatcher's career as an independent scientist dedicated to investigate cardiac development. Cardiac development is a complex process that can be wrought with defects. Congenital heart defects account for 0.5-1 % of all live births. Mutations in TBX5 cause Holt-Oram syndrome, an inherited disorder characterized by structural cardiac defects. The TBX5 transcription factor plays an important role in cardiogenesis. It can act as a cellular growth arrest signal to inhibit cell proliferation in vitro and in vivo. In this proposal, we demonstrate that mRNA and protein expression of histone deacetylase 2 (HDAC2) is upregulated byTBXS. The specific goal of the proposed research is to characterize the mechanisms underlying the interactions between and the functional contributions of TBX5 and the HDAC2 gene. We hypothesize that TBX5- dependent regulation of HDAC2 participates in TBX5 regulation of cardiomyocyte proliferation and cardiogenesis. Dr. Hatcher proposes to acquire new structural, biochemical, genomic and molecular genetic knowledge and skills to explore this critical pathway and also to determine the contribution of TBX5 along with HDAC2 to cellular proliferation and cardiogenesis. We propose: (1) to determine if TBX5 regulates HDAC2 expression through direct interactions with the HDAC2 promoter (2) to determine which TBX5 domains are required for regulation of HDAC2 expression and (3) to determine if HDAC2 overexpression is sufficient to recapitulate the effects of TBX5 on cardiac cell proliferation in vitro and in vivo. Elucidating TBX5 and HDAC2 dependent pathways in cardiac development and their contribution to regulation of cell proliferation will define key genetic events that can go awry in individuals with congenital heart malformations.
