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、循环系统和血液疾病。这并不奇怪，因为内皮是止血、血管发育、血管生成、血管紧张度以及对血管损伤和炎症的反应的中心调节器。在过去的资助周期中，我们利用了我们对内皮细胞分化和基因表达项目的长期兴趣， 填补了我们对内皮细胞命运和表型多样性是如何决定的理解上的空白。我们在上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局基因表达分析来识别负责血管发育的候选基因的结果。通过这种方法，我们建立了一个全面的候选基因列表与血管系统的发展在胚胎干细胞分化在体内。我们在这项研究中发现的许多基因是可预测的：生长因子，细胞表面标志物，转录因子和已知与血管发生相关的几种信号转导途径的成员。然而，我们也发现了一些新的参与者，包括骨形态发生蛋白（BMP）和Wnt信号通路的成员。此外，我们还鉴定并克隆了一种名为BMPER的新型内皮细胞衍生蛋白，该蛋白已成为我们下一个资助周期提出的具体目标的主要焦点。在这个资助周期中，我们将更详细地探索这些蛋白质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在内皮细胞中的分子效应的多样性;（2）表征BMPER在内皮细胞中的细胞效应的多样性;和（3）描述BMPER在调节血管血管生成信号事件和炎症中的作用。本提案的范围旨在使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。从这一建议中获得的知识应该提供关于内皮细胞从多能前体发育、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，靶向基因传递到内皮细胞和破坏和血管生成在其病理形式的机制可能会被揭示。公共卫生相关性：内皮在胚胎发生期间的血管发育和模式形成中起关键作用，并且内皮细胞通过其对血管功能和炎症、血管生成和祖细胞动力学的影响来调节血管壁稳态、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血管生成依赖性事件中重演。

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.