SIGNALS FOR RENAL ENDOTHELIAL CAPILLARY MORPHOGENESIS

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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.