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Biologic and Materials Sciences & Prosthodontics

Kaartinen Lab Current Research

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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-b 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-b 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-b-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.

Abstract 2:
The long-term goal of this proposal is to understand specific molecular mechanisms of Tgf-beta signaling that take place during palatal fusion. This is very important since failure of these processes has been shown to lead to cleft palate, one of the most common birth defects in humans. Others and we have previously shown that during palatal fusion transforming growth factor-betas (Tgf-betas) induce several downstream responses that contribute to the successful palatogenesis. This proposal focuses on the role of epithelial and mesenchymal Tgf-beta signals in coordination of palatal fusion. Our overall hypothesis is: Tgf-beta/Bmp signaling events both in the palatal mesenchyme and in the epithelium are critical for successful palatal fusion and play a concerted role during palatogenesis. We propose to test this hypothesis by five Specific Aims. In Aim 1 we propose to determine the effect of neural crest cell specific abrogation of the Tgf-b type I receptor AIk2 on palatal development. In Aim 2, we propose to define the role of Tgf-beta type I receptors AIk2 and AIk5 in the palatal midline epithelium during palatal fusion, in Aim 3 we propose to determine the role of reciprocal epithelio-mesenchymal Tgf-beta signaling during palatal fusion, in Aim 4 we propose to analyze why direct contact between the palatal epithelium and mesenchyme can bypass the Tgf-beta3 signaling defect, and finally in Aim 5 we propose to determine the role of gap junctions in Tgf-beta-induced palatal midline epithelial fusion. Our unique experimental models and the state-of-art strategy allow us to determine the role Tgf-beta signaling via AIk5 and AIk2 in palatogenesis. Collectively, the proposed experiments are likely to be of critical importance in attempting to understand the molecular bases of facial and palatal cleftings in humans, and to develop possible therapeutic approaches to treat cleft palate during the fetal period.