SMAD-INDEPENDENT TGF-BETA SIGNALING MECHANISMS IN ANGIOGENESIS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。Vary博士提出了一种新的假设，即内啡肽是一种iii型tgf - β受体，是一种bmprii介导的tgf - β受体ALK1信号的smad独立效应物，可以调节血管生成。人类内啡肽和ALK1突变可导致遗传性出血性毛细血管扩张1和2（分别为HHT1和HHT2）。此外，ALK1和BMPRII的人类突变与原发性肺动脉高压（PPH）有关。在小鼠中，ALK1和内啡肽已被证明是血管生成所必需的。综上所述，这些研究表明内啡肽（HHT1）、ALK1 （HHT2）和BMPRII （PPH）的缺陷破坏了一个共同的信号通路。C. Vary提供了强有力的初步数据来支持这一假设，并提出了两个具体目标：1)确定bmprii介导的ALK1信号反应，2)检查内啡肽和ALK1表达对血管模式的影响。这是一个高度创新的项目，有可能解决围绕血管中tgf - β信号通路的一些悖论。这些研究是C. Vary长期以来对内啡肽功能的细胞和分子生物学兴趣的延伸。该项目与COBRE的目的和目标高度相关，并将与项目1 （Lindner）和2 （Liaw）互动。可以预期，这些项目之间的协作互动将作为这些努力的结果而发展。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.