RENAL MICROVASCULAR ENDOTHELIAL CELL DIFFERENTIATION

描述：(项目摘要)肾小球和肾小管结构和功能的发展、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可见于各种疾病状态。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-生长因子相互作用的领域，以及黏附和紧密连接复合体的发展。虽然内皮细胞屏障功能的发展、维持和调节已经在功能上得到了很好的研究，但与大多数所研究的上皮细胞相比，内皮细胞的相对平坦性导致了基于形态的研究进展缓慢。内皮细胞黏附连接含有一种内皮特异性钙粘蛋白-VE-钙粘蛋白，它与(α-和β-连环蛋白、白蛋白和p120cas)形成络合物，最近的研究发现，内皮细胞的通透性受黏附连接的调节。血小板内皮细胞黏附分子-1(PECAM-1/CD31)是一种免疫球蛋白家族成员，从血管母细胞到成年期表达于内皮细胞，位于血管内皮细胞的侧缘，被认为在血管发生和血管生成的早期阶段发挥作用。在这项建议中，我们将研究PECAM-1作为β-连环蛋白结合部分的作用，以及作为调控β-连环蛋白磷酸化的支架，从而调节β-连环蛋白参与粘连连接的形成和基因表达。需要检验的假设是，PECAM-1对肾内皮细胞连接的形成、维持和动态调节是必不可少的。涉及血管内皮细胞动态选择性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用多种方法阐明，以确定PECAM-1在内皮分化和极性的发展和维持以及对缺氧损伤的反应中所起的作用。

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.