Signaling in Endothelial Growth and Angiogenesis

描述(由申请人提供)：血管内皮功能障碍导致大多数心血管、循环和血液疾病。这并不令人惊讶，因为内皮细胞是止血、血管发育、血管生成、血管运动张力以及对血管损伤和炎症反应的中央调节器。在过去的资金周期中，我们使用了几种互补的方法，利用我们对内皮细胞分化和基因表达程序的长期兴趣，填补了我们在理解内皮细胞命运和表型多样性如何决定方面的空白。我们在前一个资助周期中的一些最令人兴奋的发现来自于使用分化内皮细胞的全球基因表达分析来确定负责血管发育的候选基因的结果。通过这种方法，我们建立了一个与体内胚胎干细胞分化过程中血管系统发育相关的候选基因的全面清单。我们在这项研究中发现的许多基因都是可预测的：生长因子、细胞表面标记、转录因子和几个已知与血管生成相关的信号转导通路的成员。然而，我们也发现了一些新的成员，包括骨形态发生蛋白(BMP)和Wnt信号通路的成员。此外，我们鉴定并克隆了一种名为BMPER的新型内皮细胞前体衍生蛋白，这已成为我们下一个资金周期提出的具体目标的主要焦点。在这个资金周期中，我们将更详细地探索这些蛋白在调节内皮细胞表型中的分子作用，重点是血管系统中的BMP信号通路。该提案的目的是(1)了解BMPER在内皮细胞中分子作用的多样性；(2)表征BMPER在内皮细胞中细胞作用的多样性；以及(3)描述BMPER在调节血管新生信号事件和炎症中的作用。这项提议的范围旨在利用最先进的分子生物学技术解决相关的生物学和生理学问题。从这项建议中获得的知识应该提供关于多潜能前体细胞的内皮细胞发育、健康和疾病中的血管形成以及内皮细胞类型特异性基因表达的关键信息。此外，靶向内皮细胞的基因传递机制以及其病理形式的破坏和血管生成机制也可能被揭示。公共卫生相关性：在胚胎发育过程中，内皮细胞在血管发育和图案形成中起关键作用，而内皮细胞通过影响血管运动功能和炎症、血管生成和祖细胞动力学来调节血管壁的动态平衡、组织对缺血的反应和血管再生。我们的总体目标是确定有助于血管分化和形态发生的事件，并预期这些相同的过程在成人的血管生成依赖事件中重现。

DESCRIPTION (provided by applicant): Dysfunction of the vascular endothelium contributes to most cardiovascular, circulatory, and blood diseases. This is not surprising, as the endothelium is the central regulator of hemostasis, vascular development, angiogenesis, vasomotor tone, and the response to vascular injury and inflammation. We have used several complementary approaches during the past funding cycle taking advantage of our longstanding interest in endothelial cell differentiation and gene expression programs to fill in the gaps in our understanding of how endothelial cell destiny and phenotypic diversity are determined. Some of our most exciting findings during the previous funding cycle came from the results of using global gene expression analysis of differentiating endothelial cells to identify candidate genes that are responsible for vascular development. Through this approach, we established a comprehensive list of candidate genes associated with the development of the vascular system during embryonic stem cell differentiation in vivo. Many of the genes we identified in this study were predictable: growth factors, cell surface markers, transcription factors and members of several signal transduction pathways already known to be associated with vasculogenesis. However, we also discovered some new players, including members of the bone morphogenetic protein (BMP) and Wnt signaling pathways. In addition, we identified and cloned the novel endothelial cell precursor-derived protein called BMPER, which has become a major focus of the Specific Aims proposed for our next funding cycle. In this funding cycle, we will explore in more detail the molecular roles of these proteins in modulating endothelial cell phenotypes, with a focus on BMP signaling pathways in the vasculature. The aims of the proposal are to (1) understand the diversity of molecular effects of BMPER in endothelial cells; (2) characterize the diversity of cellular effects of BMPER in endothelial cells; and (3) delineate the role of BMPER in regulation of vascular angiogenic signaling events and inflammation. The scope of this proposal is intended to address relevant biological and physiological questions using state of the art molecular biology techniques. Knowledge gained from this proposal should provide crucial information about endothelial cell development from multipotent precursors, blood vessel formation in health and disease, and endothelial cell-type specific gene expression. In addition, mechanisms for targeted gene delivery to endothelial cells and for disruption and angiogenesis in its pathologic forms may be revealed. PUBLIC HEALTH RELEVANCE: The endothelium plays a critical role in vascular development and pattern formation during embryogenesis, and endothelial cells regulate vessel wall homeostasis, tissue response to ischemia, and vascular regeneration through their effects on vasomotor function and inflammation, angiogenesis, and progenitor cell dynamics. Our overall goal is to determine the events that contribute to vascular differentiation and morphogenesis, with the anticipation that these same processes are recapitulated in angiogenesis-dependent events in the adult.