SMAD-INDEPENDENT TGF-BETA SIGNALING MECHANISMS IN ANGIOGENESIS

血管生成中独立于 SMAD 的 TGF-β 信号传导机制

• 批准号: 7609693
• 负责人: Calvin Pardee Hull Vary
• 金额: $ 18.81万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7609693
• 关键词: ACVRL1 gene; Blood Vessels; Centers of Research Excellence; Computer Retrieval of Information on Scientific Projects Database; Data; Defect; ENG gene; Endoglin; Funding; Goals; Grant; Hereditary hemorrhagic telangiectasia; Human; Institution; Mediating; Molecular and Cellular Biology; Mus; Mutation; Pattern; Publishing; Research; Research Personnel; Resources; Signal Pathway; Signal Transduction; Source; TGF Beta Signaling Pathway; TGF beta type III receptor; Transforming Growth Factor beta Receptors; United States National Institutes of Health; angiogenesis; innovation; interest; primary pulmonary hypertension; response

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 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's Published and preliminary data support this hypothesis and the 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. Varys 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 is interactive with Projects 1 (Lindner) and 2 (Liaw). It is anticipated that rather strong collaborative interactions between these projects will continue to evolve.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 Vary 博士提出了这样的假设：内皮糖蛋白（一种 III 型 TGF-β 受体）是 BMPRII 介导的、不依赖 SMAD 的 TGF-β 受体 ALK1 信号转导调节血管生成的效应子。 人类内皮糖蛋白和 ALK1 突变会导致遗传性出血性毛细血管扩张症 1 和 2（分别为 HHT1、HHT2）。 此外，人类 ALK1 和 BMPRII 突变与原发性肺动脉高压 (PPH) 相关。 在小鼠中，ALK1 和内皮糖蛋白已被证明是血管生成所必需的。 总而言之，这些研究表明内皮糖蛋白 (HHT1)、ALK1 (HHT2) 和 BMPRII (PPH) 的缺陷会破坏常见的信号通路。 C. Vary 已发表的初步数据支持这一假设和两个具体目标：1) 识别 BMPRII 介导的 ALK1 信号传导反应，2) 检查内皮糖蛋白和 ALK1 表达对血管模式的影响。这是一个高度创新的项目，可能会解决围绕脉管系统中 TGF-β 信号通路的一些悖论。这些研究是 C. Vary 长期以来对内皮糖蛋白功能的细胞和分子生物学兴趣的延伸。该项目与 COBRE 的宗旨和目标高度相关，并与项目 1 (Lindner) 和 2 (Liaw) 互动。预计这些项目之间的强有力的协作互动将继续发展。