Kidney Vascularization-- VEGF-mediated Mechanisms

描述（申请人摘要）：血管内皮生长因子（VEGF） 功能对于血管发育至关重要。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。VEGF 在发育中的肾脏邻近的实质细胞中表达 整个胚胎生命和出生后的生命。我们发现VEGF 在后肾器官培养中诱导血管发生，VEGF是 趋化因子在肾移植过程中为迁移的内皮细胞提供方向 形态发生，这表明VEGF对于建立空间分布是重要的。 肾血管的组织。血管的分子基础 肾脏发育过程中的空间结构及VEGF在肾脏发育中的作用 上皮细胞是未知的，并且是该提议的焦点。客观 这一建议的目的是阐明介导定向的机制， 在肾器官发生和血管形成过程中内皮细胞迁移。我们 一种假设是，由肾上皮细胞产生的VECiF产生局部的 浓度梯度为内皮细胞提供化学吸引线索 迁移我们还假设VEGF支持建立并 维持有窗孔内皮细胞表型，从而有助于 调节血管渗透性。为了验证我们的假设：1）我们将 探讨内皮细胞向胚胎定向迁移的机制 肾脏，并检查肾上皮细胞VEGF系统的功能 使用迁移分析和共培养模型。2)我们将研究下游 VEGF诱导定向内皮细胞的信号机制 迁移：检查整合素、FAK和MAP激酶介导的信号的作用。 3)我们将确定是否需要建立VEGF， 维持肾小球内皮细胞的有窗孔表型 并研究相关的信号机制。拟议的实验 应提供有关VEGF诱导的定向 迁移和推进我们的知识的分子机制， 血管空间组织和肾形态发生。了解 细胞迁移的分子基础指导线索应该使我们能够 为先天性肾脏病的诊断和治疗提供新的策略 异常和癌症。

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.