TYROSINE PHOSPHATASES IN ENDOTHELIAL GROWTH CONTROL

酪氨酸磷酸酶在内皮生长控制中的作用

• 批准号: 6380564
• 负责人: TAKAMUNE TAKAHASHI
• 金额: $ 29.37万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6380564
• 关键词: angiogenesis; capillary; cell adhesion; cell growth regulation; cell line; cell migration; cell proliferation; enzyme activity; enzyme mechanism; gene expression; genetically modified animals; human tissue; intracellular transport; kidney cell; laboratory mouse; monoclonal antibody; phosphorylation; protein localization; protein tyrosine phosphatase; receptor binding; vascular endothelium

Definition of the intrinsic molecular controls that regulate angiogenic and vasculogenic blood vessel growth promises to provide targets for therapy of solid tumors, diabetic retinopathy, arthritis, skin and other diseases. Developmental assembly, remodeling and maintenance of microvascular integrity are dynamic processes regulated by endothelial responses to local environmental cues, transduced through surface receptors. One of the properties fundamental to endothelium in mature vessels is cell context dependent constraints over proliferation. We have advanced the hypothesis that an endothelial receptor tyrosine phosphatase, ECRTP/CD148, transduces cell growth arrest signals on juxtacrine contact with a counter-receptor. A monoclonal antibody, ECRTP.ab1, that specifically binds ECRTP/CD148 ectodomain sequences localizes its expression to endothelium of arteries and capillaries in kidney, and other tissues. Endothelial progenitor cells express ECRTP/CD148 prior to their incorporation into developing glomerular capillaries of kidney, and ECRTP/CD148 accumulates at inter-endothelial points of contact. Bivalent forms of ECRTP.ab1 block cultured endothelial cell proliferation and migration, inhibit angiogenesis in a mouse corneal assay, and promote dephosphorylation of intracellular tyrosine phosphoproteins. Expression of ECRTP/CD148 in deficient cell lines confers antibody-induced growth inhibition that is dependent upon intrinsic tyrosine phosphatase activity. The current proposal describes plans to: 1) define a functional counter-receptor to CD148, 2) to identify intracellular substrates of ECRTP/CD148 and their role in endothelial growth arrest, and 3) to define ECRTP/CD148 function during vascular development. Homologous recombinant ES lines and mice will define function of ECRTP/CD148 in developmental vascular assembly. These studies will extend definition of molecular controls regulating angiogenesis, and will define new molecular targets for anti-angiogenic therapies.

调节血管生成和血管生成血管生长的内在分子对照的定义有望为固体瘤，糖尿病性视网膜病，关节炎，皮肤和其他疾病的治疗提供靶标。 开发组装，重塑和维持微血管完整性是通过对局部环境线索的内皮反应调节的动态过程，该过程通过表面受体传递。 成熟血管中内皮基本的特性之一是细胞环境依赖于增殖的限制。 我们提出了这样一个假设，即内皮受体酪氨酸磷酸酶ECRTP/CD148会在与反受体接触时传达细胞生长停滞信号。 一种单克隆抗体ECRTP.AB1，该抗体特异性结合ECRTP/CD148胞外域序列将其表达定位于肾脏和其他组织中动脉和毛细血管内皮的表达。内皮祖细胞将ECRTP/CD148掺入肾脏的肾小球毛细血管之前，而ECRTP/CD148则在接触的内皮间点积聚。 ECRTP.AB1的二价形式阻断培养的内皮细胞增殖和迁移，抑制小鼠角膜测定中的血管生成，并促进细胞内酪氨酸磷酸蛋白的去磷酸化。 ECRTP/CD148在缺陷细胞系中的表达赋予抗体诱导的生长抑制，这取决于内在的酪氨酸磷酸酶活性。 当前的提案描述了：1）定义CD148的功能反受体，2）确定ECRTP/CD148的细胞内底物及其在内皮生长停滞中的作用，以及3）来定义ECRTP/CD148在血管发育过程中。 同源重组线和小鼠将定义ECRTP/CD148在发育血管组装中的功能。 这些研究将扩展调节血管生成的分子对照的定义，并将定义用于抗血管生成疗法的新分子靶标。