Activin Receptor-Like Kinase-2 in Cardiac Morphogenesis

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DESCRIPTION (provided by applicant): Congenital cardiac malformations are the most common birth defects in humans affecting about 1 in 100 newborns. While recent studies both in mice and in humans have identified several different signaling processes and transcriptional regulators that are required for appropriate cardiac development, very little is still known about interactions between these factors during heart morphogenesis, and about pathogenetic mechanisms leading to the congenital heart disease (CHD) in humans. We have previously demonstrated that the BMP type I receptor Alk2 plays a critical role both in cardiac neural crest cells as well as in endocardial cells regulating aortico-pulmonary septation and endocardial transformation (EndMT), while other investigators have demonstrated that another type I receptor mediating BMP signaling called Alk3 is playing a critical non-redundant role in cardiac outflow tract septation and endocardial transformation as well. Moreover, we have recently discovered mutations in the coding region of Alk2 and Alk3 genes in human patients suffering from CHD. However, it is currently not known, how Alk2 and Alk3-mediated BMP signaling pathways interact and cooperate with each other to regulate EndMT and how TGF-2 signaling via Alk5 is coordinated with BMP signaling in this process. In this proposal I want to test the central hypothesis that that concerted action of TGF-2 and BMP signaling is required for appropriate endocardial-to-mesenchymal transformation (EndMT) during mammalian cardiac development. In aim 1 we propose to determine the collaborative signaling via the BMP type I receptors Alk2, Alk3 in EndMT and endocardial cushion development, and in aim 2 we propose to test whether signaling via the TGF-2-type I receptor Alk5 is critical for BMP-induced endocardial EMT. Our unique experimental models and state-of-art strategy will allow us to determine the role Tgf-2/Bmp signaling in EMT during cardiac development. Collectively, the proposed experiments are likely to be of critical importance in attempting to understand the molecular bases of endocardial defects in humans, and may ultimately allow us to develop possible preventive and/or therapeutic approaches to treat congenital cardiac defects during the fetal period and to identify new therapeutic targets to treat heart disease. PUBLIC HEALTH RELEVANCE: Congenital cardiac malformations are the most common birth defects in humans affecting about 1 in 100 newborns. The proposed studies dissect the role of specific signaling mechanisms via the so called type I receptors of bone morphogenetic proteins in cardiac morphogenesis, particularly in the development of atrio-ventricular (AV) canal, which gives raise to AV valves and septa. We expect that the proposed studies will be important for understanding of the underlying molecular mechanisms that lead to congenital cardiac malformations in humans.