SMAD-INDEPENDENT TGF-BETA SIGNALING MECHANISMS IN ANGIOGENESIS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。Varie博士提出了一个新的假设，即Endoglin是一种III型转化生长因子-β受体，是BMPRII介导的SMAD非依赖的转化生长因子-β受体ALK1信号的效应器，调节血管生成。人类endoglin和ALK1突变导致遗传性出血性毛细血管扩张症1和2(分别为HHT1和HHT2)。此外，人类ALK1和BMPRII基因突变与原发性肺动脉高压(PPH)相关。在小鼠中，ALK1和endoglin已被证明是血管生成所必需的。综上所述，这些研究表明，endoglin(HHT1)、ALK1(HHT2)和BMPRII(PPH)的缺陷破坏了一个共同的信号通路。C.Varie提供了强有力的初步数据来支持这一假说，并提出了两个具体的目标：1)识别BMPRII介导的ALK1信号反应；2)研究endoglin和ALK1表达对血管模式的影响。这是一个高度创新的项目，可能会解决血管系统中围绕转化生长因子-β信号通路的一些悖论。这些研究是C.Varie？S长期以来对Enoglin功能的细胞和分子生物学兴趣的延伸。该项目与科布雷的宗旨和目标高度相关，并将与项目1(林德纳)和项目2(廖威)互动。预计由于这些努力，这些项目之间将形成相当强的协作互动。这个项目可能会迅速发展成为一个成功的R01应用程序。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Dr. Vary has proposed the novel hypothesis that endoglin, a type-III TGF-beta receptor, is a BMPRII-mediated SMAD-independent effector of TGF-beta receptor ALK1 signaling that regulates angiogenesis. Human mutations in endoglin and ALK1 result in hereditary hemorrhagic telangiectasias 1 and 2 (HHT1, HHT2 respectively). In addition, human mutations in ALK1 and BMPRII are associated with primary pulmonary hypertension (PPH). In the mouse, ALK1 and endoglin have been shown to be required for angiogenesis. Taken together, these studies suggest that defects in endoglin (HHT1), ALK1 (HHT2), and BMPRII (PPH) disrupt a common signaling pathway. C. Vary presents strong preliminary data in support of this hypothesis and proposes two specific aims: 1) to identify BMPRII-mediated ALK1 signaling responses and 2) to examine the consequences of endoglin and ALK1 expression on vascular patterning. This is a highly innovative project that is likely to resolve some of the paradoxes surrounding TGF-beta signaling pathways in the vasculature. These studies are an extension of C. Vary¿s long-standing interest in the cell and molecular biology of endoglin function. The project is highly relevant to the aims and goals of this COBRE and will be interactive with Projects 1 (Lindner) and 2 (Liaw). It is anticipated that rather strong collaborative interactions between these projects will evolve as a result of these efforts. This project will likely evolve rapidly into a successful R01 application.