CELLULAR DETERMINANTS OF GLOMERULAR PERMSELECTIVITY

肾小球是一个复杂的过滤器，具有非常高的水力。 导电性好，大分子渗透性低。不正常的 水力传导性和大分子渗透性伴随着大多数类型 进行性肾脏疾病，但对生理学和 肾小球通透性屏障的调节不是很完善。 我建议测试一种假设，即影响肾小球的激素 体内的功能是通过它们对肾小球细胞的作用来实现的 滤过屏障和细胞内过程，如钙通量 和肌动蛋白细胞骨架的聚合是潜在的机制，通过 这些细胞可能会调节通透性。我会在体外利用两个 在我的赞助人的实验室开发的技术，可以促进直接 评估肾小球滤过屏障，独立于 体内存在的潜在混杂变量，如局部和 全身荷尔蒙和血流动力学。此外，我将使用共焦 显微镜下评估两种潜在细胞内的重要性 通透性、细胞内钙通量和血管内皮细胞聚合的介体 肾小球系膜细胞和肾小管上皮细胞中肌动蛋白的细胞骨架 完整的活肾小球的光学横切面。 具体而言，我将回答以下问题： 一、影响肾小球的系统性因素血管紧张素II和胰岛素样生长因子-1 功能，对肾小球通透性屏障有直接影响吗？ 细胞内钙离子和肌动蛋白细胞骨架对肾小球的调节 渗透性？

The glomerulus is a complex filter with remarkably high hydraulic conductivity and low macromolecular permeability. Abnormalities of hydraulic conductivity and macromolecular permeability accompany most types of progressive renal disease, yet the understanding of the physiology and regulation of the glomerular permeability barrier is not well developed. I propose to test the hypothesis that hormones which influence glomerular function in vivo do so by their action on cells of the glomerular filtration barrier and that intracellular processes such as calcium flux and polymerization of the actin cytoskeleton are potential mechanisms by which these cells might regulate permeability. I will utilize two in vitro techniques developed in my sponsor's laboratory which facilitate direct assessment of the glomerular filtration barrier, independently of potentially confounding variables present in vivo, such as local and systemic hormones and hemodynamics. In addition, I will use confocal microscopy to assess the importance of two potential intracellular mediators of permeability, intracellular calcium flux and polymerization of the actin cytoskeleton in discrete mesangial and epithelial cells in thin optical cross sections of intact, living glomeruli. Specifically, I will address the following questions: I.Do Angiotensin II and IGF-1, systemic factors which influence glomerular function, have a direct effect on the glomerular permeability barrier? II.Do intracellular calcium and the actin cytoskeleton modulate glomerular permeability?