Congenital heart disease is the most frequent and deadly birth defect. Patients that survive past infancy often progress to develop advanced heart failure requiring specialized treatment including cardiac transplantation. A full understanding of the transcriptional networks that direct cardiac progenitors during heart development will enhance our understanding of both normal cardiac function and pathological states. These finding will also have important applications related to cell based therapies and the treatment of congenital heart disease. Furthermore, a number of shared transcriptional pathways or networks have been proposed between development and regeneration of tissues such as the heart. We have utilized transgenic technology to isolate and characterize cardiac progenitor cells from the developing mouse heart. We propose to extend our analyses of the cardiac progenitor cell population in the developing mouse heart to define specific transcriptional networks of cardiovascular development. We have identified Etsrp71 as a potential downstream target of Nkx2-5. We have also generated Etsrp71 deficient embryos that are nonviable and have pertubated cardiovascular development. My long term goal is to further elucidate the molecular mechanisms regulating the progenitor cell populations involved in cardiovascular development. We hypothesize that Nkx2-5 regulated networks direct discrete stages of cardiac morphogenesis. We further predict that Etsrp71 is a direct downstream target of Nkx2-5, identifies the hemangioblast population and is a master regulator of the endothelial/endocardial lineages. In these proposed studies, we take an innovative approach to examine these hypotheses and employ emerging technologies to isolate and characterize the cardiac progenitor cell population in the developing murine heart. To address of my long term goal we will address the following specific aims: 1) To define the upstream transcriptional regulatory cascade of Etsrp71. 2) To determine whether Etsrp71 is a marker of the hemangioblast. 3) To confirm that Sox 7 and Sox 17 are direct downstream targets of Etsrp71.
These aims are distinctive within this field of research for several reasons. We have utilized transgenic, FACS and transcriptome analyses to identify, isolate and comprehensively define the molecular signature of the cardiac progenitor cell population. We have identified Etsrp71 as a direct downstream target of Nkx2-5. Our strategy will be to define the Nkx2-5-Etsrp71 transcriptional network in the cardiac progenitors and further define the functional role of Etsrp71 in cardiovascular development. These proposed studies will further our understanding of the transcriptional cascades and signaling pathways during embryogenesis. The Clinical Scientist Development Award (CSDA) will aid in my long-term goal to attain independent status as a clinician scientist. This award will enable me to continue translating my in-vitro preliminary data to in-vivo transgenic models and provide the opportunity to begin to translate scientific findings to clinical practice.
My goal is to further elucidate the molecular mechanisms regulating the progenitor cell populations involved in cardiovascular development. I also hope that through my continued research in cardiovascular development I will provide discoveries that will help improve the clinical outcome of adults with congenital heart disease.
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