Congenital heart defects affect 1/200 live births and many of these defects have poor surgical outcomes. Recently it has been shown that surgical cures during the neonatal or pediatric period can result in significant morbidity and mortality later in adulthood . In order to have better patient outcomes in the future it is evident that alternate therapies are needed for the treatment and prevention of congenital heart diseases. To create useful therapeutics directed at preventing or treating these defects, the molecular events controlling normal and aberrant heart development must be uncovered. The retinoid X receptor alpha knockout mouse (RXRa-/-) shows cardiac defects which phenocopy human cases of congenital heart disease. In this mouse, proper chamber and outflow tract (OFT) septation does not occur due to hypoplasticity of cardiac cushion tissue and fetal death occurs in late-midgestation due to cardiac failure . Transforming growth factor beta 2 (TGF(32), a cytokine affecting cellular growth, differentiation, and apoptosis is upregulated in the hearts of RXRa-/- versus wild type (WT) animals . This increase in TGF02 signaling is related to increased apoptosis in the RXRa-/- heart and these knockouts, when bred onto a TGFB2 background show an attenuation of OFT septation defects . These data suggest that the retinoid and TGFB pathways intersect to regulate cardiac development and preliminary studies support the potential for direct interaction between retinoid signaling and signaling molecules downstream of TGFB2 (i.e. Smad2) . The proposed study will establish the nature of these interactions and their relevance during heart development. We hypothesize that direct interactions between TGFB and retinoid signaling regulate critical aspects of cardiac development particularly OFT remodeling. Spatial and temporal characterization of TGFB and retinoid pathway players will be performed to determine any relevant canonical feedback mechanisms at work in the RXRa-/-. Additionally, the effects of heterozygosity for Smad2 and SmadS on the RXRa-/- will be investigated on the morphological and molecular levels. Public Health Relevance: These experiments will yield a better understanding of the molecular events controlling normal and aberrant cardiac development. It is our hope that discoveries generated from these studies will lead to the eventual development of therapeutics to better treat congenital heart disease.
|Hoover, Loretta L; Burton, Elizabeth G; O'Neill, Megan L et al. (2008) Retinoids regulate TGFbeta signaling at the level of Smad2 phosphorylation and nuclear accumulation. Biochim Biophys Acta 1783:2279-86|