SIGNALS FOR RENAL ENDOTHELIAL CAPILLARY MORPHOGENESIS

毛细血管内皮细胞的增殖和分化是一个重要的生物学过程。 发展的基本过程，专门的器官功能， 也会痊愈 细胞分化功能紊乱和增殖 毛细血管内皮细胞是病理过程中不可或缺的一部分，范围包括 肿瘤、纤维化/硬化性疾病、糖尿病性神经病变和 肾病 内皮细胞处理来自介质的细胞外信号 通过细胞内信号的整合功能 尚未定义的系统。 这一提议涉及到以下假设： 特定的内皮酪氨酸激酶信号事件介导 毛细血管样管形成（CTF）。 细胞型限制性酪氨酸激酶 在许多发育系统中调节细胞命运决定， 增殖和分化。 使用培养的人肾 微血管内皮细胞，我们已经表明：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， 和3）一种新的假定的内皮酪氨酸激酶，ETK，在 支持CTF的限制条件。 我们建议：1）获得一个完整的 长度ETK cDNA，产生ETK抗体，2）鉴定 胚胎发育过程中ETK的表达，血管生成，以及3） 确定这种推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基本过程的定义 并建立工具来探索这一过程的病理变化， 糖尿病和癌症

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.