REGULATION OF EMBRYONIC ANGIOGENESIS BY SMAD PROTEINS

SMAD 蛋白对胚胎血管生成的调节

• 批准号: 6390885
• 负责人: ROBERT J LECHLEIDER
• 金额: $ 25.94万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390885
• 关键词: angiogenesis; developmental genetics; embryogenesis; genetically modified animals; growth factor receptors; laboratory mouse; mammalian embryology; receptor binding; transcription factor; transforming growth factors

Blood vessels are formed by two processes. Vasculogenesis is the creation of new vessels from differentiating mesoderm, and angiogenesis is the extension and remodeling of existing vessels. Although angiogenesis is an essential component of normal physiological processes and responses to injury, pathological disturbances of angiogenesis underlie tumor development, hereditary vascular disorders and other diseases. The molecular basis of angiogenesis remains incompletely understood despite recent advances. Although numerous receptor and ligand families are essential in mediating angiogenesis, few intracellular signaling intermediates have been demonstrated to be specific or essential for this process. Cytokines of the TGF- beta superfamily, which signal exclusively through a unique set of receptor serine-threonine kinases, play important roles in many developmental processes, including angiogenesis. TGF-beta family ligands transmit their signals directly from cell surface receptors to the nucleus by a highly conserved family of transcription factors called Smads. Published data and our preliminary experiments demonstrate that two of these proteins, Smad1 and Smad5 are essential for angiogenesis in the developing murine embryo. Smad1 and Smad5 are key mediators of angiogenesis, and are among the first signaling intermediates to be identified as essential for this process. Our long range goal is identification of upstream activators and downstream effectors of Smad1- and Smad5-mediated angiogenesis. Our hypothesis is that during embryonic angiogenesis, Smad1 and Smad5 mediate a TGF-beta receptor-activated signaling pathway, which, through interaction with specific DNA binding proteins, activates or represses target genes essential for angiogenesis in the developing mouse embryo. We will use a combination of genetic, cell biological and biochemical techniques to define the signaling pathways that are mediated by Smad1 and Smad5 during embryonic angiogenesis.

血管由两个过程形成。 血管发生是指中胚层分化产生新的血管，血管生成是指已有血管的延伸和重塑。虽然血管生成是正常生理过程和对损伤的反应的重要组成部分，但血管生成的病理性紊乱是肿瘤发展、遗传性血管病症和其它疾病的基础。血管生成的分子基础仍然不完全理解，尽管最近的进展。 虽然许多受体和配体家族在介导血管生成中是必不可少的，但很少有细胞内信号传导中间体被证明是特异性的或对该过程是必需的。 TGF-β超家族的细胞因子仅通过一组独特的受体丝氨酸-苏氨酸激酶发出信号，在许多发育过程中发挥重要作用，包括血管生成。 TGF-β家族配体通过高度保守的称为Smads的转录因子家族将其信号直接从细胞表面受体传递到细胞核。 已发表的数据和我们的初步实验表明，这些蛋白质中的两个，Smad 1和Smad 5是在发育中的小鼠胚胎血管生成所必需的。 Smad 1和Smad 5是血管生成的关键介质，是第一个被确定为该过程所必需的信号中间体。我们的长期目标是识别Smad 1和Smad 5介导的血管生成的上游激活因子和下游效应因子。我们的假设是，在胚胎血管生成过程中，Smad 1和Smad 5介导TGF-β受体激活的信号通路，通过与特异性DNA结合蛋白的相互作用，激活或抑制发育中小鼠胚胎血管生成所必需的靶基因。 我们将使用遗传学，细胞生物学和生物化学技术相结合，以确定由Smad 1和Smad 5在胚胎血管生成过程中介导的信号通路。