RENAL MICROVASCULAR ENDOTHELIAL CELL DIFFERENTIATION

项目摘要：肾小球和肾小管的结构和功能的发展、维持和重建是人们非常感兴趣和研究的领域。可逆性肾小球和肾小管功能障碍在多种疾病状态下均有表现。在过去的五年中，我们对肾功能的了解主要集中在上皮细胞-细胞、细胞-基质和细胞生长因子的相互作用以及粘附物和紧密连接复合物的发展方面。虽然内皮屏障功能的发育、维持和调节已经在功能上得到了很好的研究，但与大多数上皮细胞相比，内皮细胞的相对平坦性导致基于形态学的研究进展较慢。内皮细胞粘附连接含有内皮特异性钙粘蛋白- ve -钙粘蛋白，它与α -和β -连环蛋白、血小板红蛋白和p120cas复合物，最近的研究发现内皮的通透性是通过粘附连接的调节来调节的。血小板内皮细胞粘附分子-1 （PECAM-1 /CD31）是Ig家族成员之一，在成血管期至成年期的内皮细胞上表达，位于内皮细胞的外侧边界，被认为在血管发生和血管生成的早期阶段发挥作用。在本提案中，我们将研究PECAM-1作为β -连环蛋白结合片段的作用，以及作为调节β -连环蛋白磷酸化的支架，从而调节β -连环蛋白参与粘附连接形成和基因表达。要验证的假设是PECAM-1对肾内皮细胞连接的形成、维持和动态调节至关重要。血管内皮细胞中涉及动态选择性PECAM-1酪氨酸和丝氨酸/苏氨酸磷酸化/去磷酸化的信号通路将通过多种方法阐明，以确定PECAM-1在内皮分化和极性的发展和维持以及缺氧损伤反应中的作用。

Description: (Abstract of the project) The development, maintenance and reestablishment of renal glomerular and tubular structure and function are areas of intense interest and investigation. Reversible renal glomerular and tubular dysfunctions are noted in a variety of disease states. Advances in our understanding of renal function in the last five years have mainly been in the areas of epithelial cell-cell, cell-matrix and cell-growth factor interactions and in the development of adherens and tight junctional complexes. While the development, maintenance and regulation of endothelial barrier function has been well-studied functionally, the relative flatness of the endothelial cell compared to most epithelial cells studied has resulted in slower progress in morphological-based investigations. Endothelial cell adherens junctions contain an endothelial specific cadherin - VE-cadherin which complexes to (alpha- and beta-catenin, plakoglobin and p120cas and recent studies have found that endothelial permeability is modulated by regulation of the adherens junctions. Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1 /CD31), an Ig family member expressed on endothelia from the hemangioblast stage through adulthood, is located at lateral borders of endothelial cells and is thought to play a role in the early stages of vascular genesis and angiogenesis. In this proposal we will examine the role of PECAM-1 as a beta-catenin binding moiety and as a scaffolding upon which beta-catenin phosphorylation is regulated, thus regulating beta-catenin's participation in adherens junction formation and gene expression. The hypothesis to be tested is that PECAM-1 is essential for the formation, maintenance and dynamic modulation of renal endothelial cell junctions. Signaling pathways involving dynamic selective PECAM-1 tyrosine and serine/threonine phosphorylation/ dephosphorylation in vascular endothelial cells will be elucidated using a variety of methods to determine the roles of PECAM-1 in the development and maintenance of endothelial differentiation and polarity and during responses to hypoxic injury.