Transcriptional Regulation of Cardiac Morphogenesis

描述（由申请人提供）：先天性心脏畸形是最常见的出生缺陷，它会导致儿童和成人的晚期心力衰竭。加强对心脏发育过程中指导心脏祖细胞的转录网络的理解，将在基于细胞的治疗和先天性心脏病的治疗中具有重要的应用。此外，许多平行的转录途径或网络已被提出用于组织的产生和再生，如心脏。基于这些原因，我们预测心脏发育中心脏祖细胞转录调控机制的定义将增强我们对心脏发生、先天性心脏病和心肌再生的理解。我们最近利用转基因技术从发育中的小鼠心脏中分离和表征心脏祖细胞。我们已经确定Etsrp71是Nkx2-5的潜在下游靶点，并产生了不能存活且心血管发育受到干扰的Etsrp71缺陷胚胎。我们的主要假设是Nkx2-5调节网络直接心脏形态发生的离散阶段。我们进一步预测，Etsrp71是Nkx2-5的直接下游靶点，是心内膜/内皮细胞谱系的主要调节剂。在这些拟议的研究中，我们采用创新的方法来检验这些假设，并采用新兴技术来定义Nkx2-5 - Etsrp71级联在心血管发展中的作用。为了验证这些假设，我们将解决以下具体目标：1)定义从发育中的小鼠心脏分离的心脏祖细胞中的Nkx2.5转录调控级联。2)明确Etsrp71在胚胎发生过程中的功能作用。3)确定Etsrp71是否是心内膜/内皮谱系的主要调节因子。这些研究将增强我们对转录网络和信号通路的作用的理解，这些转录网络和信号通路机制地调节心脏祖细胞（CPC）群体在发育过程中获得心血管命运。此外，这些研究的结果将为先天性心脏病和晚期心力衰竭的治疗策略提供平台。公共卫生相关性：先天性心脏病是常见且致命的。增加对心脏发育过程中直接心脏祖细胞和干细胞的网络的理解将对先天性心脏病的治疗具有重要的治疗应用。由于这些祖细胞的调控在很大程度上是未知的，这一建议将破解控制心脏祖细胞的分子途径，这可能最终作为一个平台来增强心脏畸形和晚期心力衰竭患者的再生过程。

DESCRIPTION (provided by applicant): Congenital cardiac malformation is the most frequent birth defect and it contributes to advanced heart failure in the pediatric and adult population. An enhanced understanding of the transcriptional networks that direct cardiac progenitors during heart development will have important applications related to cell based therapies and the treatment of congenital heart disease. Furthermore, a number of parallel transcriptional pathways or networks have been proposed for the generation and regeneration of tissues such as the heart. For these reasons, we predict that the definition of the transcriptional regulatory mechanisms of cardiac progenitor cells in the developing heart will enhance our understanding of cardiogenesis, congenital heart disease and myocardial regeneration. We have recently utilized transgenic technology to isolate and characterize cardiac progenitor cells from the developing mouse heart. We have identified Etsrp71 as a potential downstream target of Nkx2-5 and generated Etsrp71 deficient embryos that are nonviable and have perturbed cardiovascular development. Our principle hypothesis is that Nkx2-5 regulated networks direct discrete stages of cardiac morphogenesis. We further predict that the Etsrp71 is a direct downstream target of Nkx2-5 and is a master regulator of the endocardial/endothelial lineages. In these proposed studies, we take an innovative approach to examine these hypotheses and employ emerging technologies to define the role of the Nkx2-5 - Etsrp71 cascade and cardiovascular development. To examine these hypotheses, we will address the following specific aims: 1) To define the Nkx2.5 transcriptional regulatory cascades in cardiac progenitor cells isolated from the developing murine heart. 2) To define the functional role of Etsrp71 during embryogenesis. 3) To determine whether Etsrp71 is a master regulator of the endocardial/endothelial lineage. These studies will enhance our understanding of the role of transcriptional networks and signaling pathways that mechanistically regulate cardiac progenitor cell (CPC) populations to acquire a cardiovascular fate during development. In addition, the results of these studies will serve as a platform for therapeutic strategies directed towards congenital heart disease and advanced heart failure. PUBLIC HEALTH RELEVANCE: Congenital heart disease is common and deadly. An increased understanding of the networks that direct cardiac progenitors and stem cells during heart development will have important therapeutic applications for the treatment of congenital heart disease. As the regulation of these progenitor cells are largely unknown, this proposal will decipher the molecular pathways that govern cardiac progenitors, which may ultimately serve as a platform to enhance the regenerative process in patients with cardiac malformations and advanced heart failure.