Kidney Vascularization-- VEGF-mediated Mechanisms

说明(申请人摘要)：血管内皮生长因子(VEGF) 功能对血管发育至关重要。然而，分子事件 协调血管发育和肾脏形态发生的机制尚不清楚。血管内皮生长因子 在与发育中的肾脏相邻的实质细胞中表达 贯穿胚胎生命和出生后生命的血管系统。我们证明了血管内皮生长因子 在后肾器官培养中诱导血管生成，而血管内皮生长因子是一种 趋化物质在肾脏过程中为内皮细胞迁移提供方向 形态发生，提示血管内皮生长因子在建立空间分布中起重要作用 肾血管系统的组织。血管的分子基础 肾脏发育过程中的空间组织及血管内皮生长因子在肾脏中的作用 上皮细胞是未知的，是这项提议的重点。目标是 这一建议的目的是阐明介导定向的机制 肾器官发生和血管形成过程中内皮细胞的迁移。我们的 假说是由肾上皮细胞产生的VECiF产生局部 浓度梯度为内皮细胞提供趋化线索 迁移。我们还假设，血管内皮生长因子支持建立和 维持开窗内皮细胞的表型，从而有助于 对血管通透性的调节。为了检验我们的假设：1)我们将 内皮细胞向胚胎定向迁移机制的研究 并检测肾上皮细胞中血管内皮生长因子系统的功能 使用迁移分析和共培养模式。2)我们将研究下游 血管内皮生长因子诱导内皮细胞定向生长的信号机制 迁移：研究整合素、FAK和MAP激酶介导的信号的作用。 3)我们将确定是否需要血管内皮生长因子来建立和 肾小球内皮细胞开窗表型的维持 并研究相关的信号转导机制。拟议中的实验 应提供有关血管内皮生长因子诱导的定向的基本信息 迁移和提高我们对控制的分子机制的认识 血管空间组织与肾脏形态发生。了解 细胞迁移指导线索的分子基础应该使我们能够 为先天性肾脏的诊断和治疗制定新的策略 畸形和癌症。

DESCRIPTION (Applicant's abstract): Vascular endothelial growth factor (VEGF) function is critical for vascular development. However, the molecular events that coordinate vascular development and kidney morphogenesis are unknown. VEGF is expressed in parenchymal cells contiguous to the developing kidney vasculature throughout embryonic life and postnatal life. We showed that VEGF induces vasculogenesis in metanephric organ culture and that VEGF is a chemoattractant providing direction to migrating endothelial cells during renal morphogenesis, suggesting that VEGF is important to establish the spatial organization of the renal vasculature. The molecular basis of the vascular spatial organization in the developing kidney and the function of VEGF in renal epithelial cells are unknown and are the focus of this proposal. The objective of this proposal is to elucidate the mechanisms mediating directional endothelial cell migration during kidney organogenesis and vascularization. Our hypothesis is that VECiF produced by renal epithelial cells generates local concentration gradients providing a chemoattractive cue for endothelial cell migration. We also postulate that VEGF supports the establishment and maintenance of fenestrated endothelial cell phenotype and thereby contributes to the regulation of vascular permeability. To test our hypotheses: 1) we will study the mechanism of directional endothelial cell migration towards embryonic kidneys and examine the function of the VEGF system in renal epithelial cells using migration assays and co-culture models. 2) We will study the downstream signaling mechanisms involved in VEGF-induced directional endothelial cell migration: examine the role of integrins, FAK and MAP kinase mediated signals. 3) We will determine whether VEGF is required for the establishment and maintenance of the fenestrated phenotype of glomerular endotheial cells in vitro and study the signaling mechanisms involved. The proposed experiments should provide fundamental information regarding VEGF-induced directional migration and advance our knowledge of the molecular mechanisms governing vascular spatial organization and renal morphogenesis. Understanding the molecular basis of guidance cues for cell migration should enable us to generate new strategies for diagnosis and treatment of congenital renal abnormalities and cancer.