Regulation of cardiovascular transcription

描述（由申请人提供）：心血管缺陷是美国最大的一类先天性异常，预防这些缺陷的努力需要更好地了解控制心脏和血管系统形成的遗传途径。同样，努力再生心脏组织，或选择性地抑制或诱导血管系统的生长，需要更深入地了解控制这些谱系形成的胚胎程序。这些研究的长期目标是确定控制心血管系统形成的遗传途径。本研究主要探讨转录因子MEF 2C在心脏和血管发育中的转录调控和功能。Mef 2c在心前中胚层中心肌细胞的初始特化后不久在心脏和血管内皮中表达，并且在血管发生开始后不久在脉管系统中表达。Mef 2c是参与分化的早期因子，可能是谱系特异性决定因子的直接转录靶点。在小鼠中靶向破坏mef 2c会导致妊娠中期的胚胎死亡，这些小鼠表现出严重的心脏和血管缺陷。然而，尚不清楚这两种缺陷是否是由于该组织中对mef 2c的主要需求。使用小鼠mef 2c的条件靶向等位基因，这些研究中提出的工作将使用Tie 2-Cre特异性地在内皮细胞中去除mef 2c功能，并将使用本申请中定义的新型前心区转录增强子来指导Cre介导的前心区mef 2c切除。这里提出的工作也将定义两个新的转录增强子从小鼠mef 2c基因的调节，其中一个是专门在血管内皮细胞和其他仅限于前心脏领域，使用转基因小鼠的方法。该提议的具体目的是：1）确定mef 2c在前心野和血管内皮中的功能需求。该提议旨在检验以下假设：在mef 2c缺失小鼠中观察到的心脏异常是由于前心野发育中的原发性缺陷，并且mef 2c功能是血管发育所需的内皮细胞。2)明确mef 2c在心前区和血管内皮的调节作用。这些研究将确定赋予mef 2c前心野增强子空间限制的转录调节因子，并将确定来自mef 2c的血管内皮增强子的上游调节因子。3)确定成人心脏前心野mef 2c表达细胞来源的区域。

DESCRIPTION (provided by applicant): Cardiovascular defects represent the largest class of congenital anomalies in the United States and efforts to prevent these defects require a greater understanding of the genetic pathways controlling the formation of the heart and vascular systems. Likewise, efforts to regenerate cardiac tissue, or to selectively inhibit or induce the growth of the vasculature require a deeper understanding of the embryonic programs that control the formation of these lineages. The long-term goal of these studies is to define the genetic pathways that control the formation of the cardiovascular system. This proposal focuses on the transcriptional requlation and function of the transcription factor MEF2C in cardiac and vascular development. Mef2c is expressed in the heart and vascular endothelium shortly after the initial specification of myocardial cells in the precardiac mesoderm and in the vasculature shortly after the initiation of vasculogenesis. Mef2c is an early factor involved in differentiation and may be a direct transcriptional target of lineage specific determination factors. Targeted disruption of mef2c in the mouse results in embryonic lethality at midgestation and these mice display profound cardiac and vascular defects. However, it is not clear whether both of these defects are due to a primary requirement for mef2c in that tissue. Using a conditionally targeted allele of mouse mef2c, the work proposed in these studies will remove mef2c function specifically in endothelial cells using Tie2-Cre and will use a novel anterior heart field transcriptional enhancer defined in this application to direct Cre-mediated excision of mef2c in the anterior heart field. The work proposed here will also define the regulation of two novel transcriptional enhancers from the mouse mef2c gene, one of which is exclusively expressed in the vascular endothelium and the other that is restricted only to the anterior heart field, using transgenic approaches in mice. The specific aims of this proposal are: 1) To determine the requirement of mef2c function in the anterior heart field and in the vascular endothelium. This proposal is designed to test the hypotheses that the cardiac abnormalities observed in mef2c null mice are due to primary defects in anterior heart field development and that mef2c function is required in endothelial cells for vascular development. 2) To define the requlation of mef2c in the anterior heart field and the vascular endothelium. These studies will identify the transcriptional regulators that confer spatial restriction to the mef2c anterior heart field enhancer and will identify the upstream regulators of a vascular endothelial enhancer from mef2c. 3) To determine the regions of the adult heart derived from the mef2c-expressing cells in the anterior heart field.