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，可导致儿童和成人人群的晚期心力衰竭。在心脏发育过程中指导心脏祖细胞的转录网络的增强理解将具有与基于细胞的疗法和先天性心脏病的治疗相关的重要应用。此外，已经提出了许多平行的转录途径或网络用于组织如心脏的产生和再生。基于这些原因，我们预测，心脏祖细胞在发育中的转录调控机制的定义将提高我们对心脏发生，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鉴定心脏祖细胞。我们已经确定了Etsrp 71作为Nkx 2 -5的潜在下游靶点，并产生了不能存活并扰乱心血管发育的Etsrp 71缺陷胚胎。我们的主要假设是Nkx 2 -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Etsrp 71是Nkx 2 -5的直接下游靶点，并且是内皮细胞/内皮细胞谱系的主要调节因子。在这些拟议的研究中，我们采取创新的方法来检验这些假设，并采用新兴技术来定义Nkx 2 -5 -Etsrp 71级联反应和心血管发育的作用。为了检验这些假设，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Etsrp 71在胚胎发生过程中的功能作用。3)确定Etsrp 71是否是内皮细胞/内皮细胞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械地调节心脏祖细胞（CPC）群体在发育过程中获得心血管命运。此外，这些研究的结果将作为针对先天性心脏病和晚期心力衰竭的治疗策略的平台。公共卫生相关性：先天性心脏病是常见和致命的。对在心脏发育过程中指导心脏祖细胞和干细胞的网络的进一步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，该提案将破译控制心脏祖细胞的分子途径，这可能最终成为增强心脏畸形和晚期心力衰竭患者再生过程的平台。

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.