Congenital heart defects (CHD) are common in children, with an incidence of approximately 8 cases per 1000 live births. Atrial septal defects (ASDs) are a prevalent form of CHD. The overall objective of this project is to investigate the molecular signaling network between the odd-skipped related 1 (Osr1;Odd1) and Tbx5-Hedgehog (Hh) pathway in the development of atrial septum. Mutations in Tbx5 cause Holt-Oram syndrome (HOS) in humans, characterized by atrial or ventricular septal defects in the heart. Hegdehog (Hh)-receiving cells in the posterior second heart field (pSHF) have been shown to define a pool of atrial septal progenitors. In preliminary results, we found that Tbx5 was required in the posterior pSHF, specifically in Hh-receiving cells, in order for normal atrial septation to occur. This finding is at least partially due to the role of Tbx5 in regulating the cel cycle progression of the atrial septal progenitors. Also, overexpression of Hh signaling in atrial progenitors rescues ASDs of Tbx5 knockout embryos, suggesting a signaling cascade from Tbx5 down to Hh- pathway. Expression of Osr1 at the dorsal mesocardium overlaps with expression of Tbx5 and Gli1. Importantly, it has been shown that Osr1 knockout mouse embryos fail to form atrial septum. We further demonstrated that Tbx5 directly interact with Osr1 in atrial septation. Thus, there has been a genetic implication of Osr1 in atrial septation, but th mechanistic role of Osr1 in atrial septation remains unknown and is a focus of the proposed research. Our central working hypothesis is that Osr1 interacts with Tbx5 and Hh signaling pathway in the development of atrial septum. To test this hypothesis, we propose to uncover the roles for Osr1 in regulating the migration, proliferation and survival of atrial septum progenitor cells. Furthermore, we will identify the interaction of Osr1 between Hh signaling in atrial septal progenitors during atrial septation. To approach this problem, we will use genetic mosaic and immunohistochemistry techniques to study morphological alterations, and we will use molecular and genetic approaches to identify the mechanisms by which specific atrial septal morphologies are sculpted during development. This proposed research will lay the groundwork for our long-term goal in understanding the molecular network required in the cardiac progenitor specification. This significant research will be performed by undergraduate students and is expected to substantially advance our understanding on cardiac progenitor cell specification, the molecular basis of atrial septation, and the ontogeny of atrial septal defects.
As a group, atrial septal defects (ASDs) are detected in 1 child per 1,500 live births and make up 30 to 40% of all congenital heart disease that is seen in adults. The proposed research is relevant to public health because the project aims on studying the molecular interactions of Osr1, Tbx5 and Hh-pathway, whose mutations lead to ASDs in mouse model, and mutation of Tbx5 causes Holt-Oram syndrome in human, characterized of congenital heart disease, with a major form of ASDs. Thus, the proposed study is relevant to NIH's mission that pertains to develop fundamental knowledge that provides insights into the ontogeny and prevention of ASDs.
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