SIGNALS FOR RENAL ENDOTHELIAL CAPILLARY MORPHOGENESIS

肾内皮毛细血管形态发生的信号

基本信息

批准号：
2414853
负责人：
TOM DANIEL
金额：
$ 18.04万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-05-01 至 1998-04-30
项目状态：
已结题

项目摘要

Proliferation and differentiation of capillary endothelial cells is a fundamental process underpinning development, specialized organ function, and would healing. Disordered differentiated function and proliferation of capillary endothelia are integral to pathological processes ranging from neoplasms, to fibrosing/sclerosing diseases, to diabetic neuropathy and nephropathy. Endothelial cells process extracellular cues from mediators of angiogenesis through the integrated function of intracellular signaling systems which are yet undefined. This proposal addresses the hypothesis that specific endothelial tyrosine kinases signal events mediating capillary-like tube formation (CTF). Cell-type restricted tyrosine kinases regulate cell fate determination in many developmental systems by affecting proliferation and differentiation. Using cultured human renal microvascular endothelial cells, we have shown: 1) tyrosine kinase inhibitors block endothelial capillary morphogenesis, 2) distinct tyrosine phosphoproteins are detected under restricted conditions supporting CTF, and 3) a novel putative endothelial tyrosine kinase, ETK, is induced under restricted conditions which support CTF. We propose; 1) to obtain a full length cDNA for ETK, generate ETK antibodies, 2) to identify patterns of ETK expression during embryonic development, angiogenesis, and 3) to determine whether this putative tyrosine kinase mediates expression of marker gene products reflecting CTF. These studies will provide molecular definition of the essential process of endothelial capillary morphogenesis and establish tools to explore pathological alterations of this process in diabetes and cancer.

毛细血管内皮细胞的增殖和分化是支撑发育的基本过程、专门的器官功能、并会痊愈。分化功能和增殖紊乱毛细血管内皮细胞是病理过程不可或缺的组成部分，包括肿瘤、纤维化/硬化性疾病、糖尿病神经病变和肾病。内皮细胞处理来自介质的细胞外信号通过细胞内信号传导的整合功能促进血管生成尚未定义的系统。该提案解决了假设特定的内皮酪氨酸激酶信号事件介导毛细管样管形成（CTF）。细胞类型限制性酪氨酸激酶通过影响许多发育系统中的细胞命运决定增殖和分化。使用培养的人肾微血管内皮细胞，我们已经证明：1）酪氨酸激酶抑制剂阻断内皮毛细血管形态发生，2) 不同的酪氨酸在支持 CTF 的限制条件下检测磷蛋白， 3) 一种新的假定的内皮酪氨酸激酶，ETK，是在以下条件下诱导的：支持CTF的限制条件。我们建议； 1）获得完整的 ETK 的 cDNA 长度，生成 ETK 抗体，2) 识别模式 ETK 在胚胎发育、血管生成过程中的表达，以及 3) 确定该假定的酪氨酸激酶是否介导反映CTF的标记基因产物。这些研究将提供分子内皮毛细血管形态发生的基本过程的定义并建立工具来探索这一过程的病理改变糖尿病和癌症。