CELLULAR DETERMINANTS OF GLOMERULAR PERMSELECTIVITY

肾小球是一个复杂的过滤器， 导电性和低的大分子渗透性。 异常 水力传导性和大分子渗透性伴随大多数类型 进行性肾病，但对生理学和 肾小球渗透性屏障的调节没有得到很好的发展。 我提议检验影响肾小球的激素 在体内的作用是通过它们对肾小球细胞的作用来实现的。 过滤屏障和细胞内过程如钙流 和肌动蛋白细胞骨架的聚合是潜在的机制， 这些细胞可能调节渗透性。 我将利用两个体外 在我的申办者的实验室开发的技术， 肾小球滤过屏障的评估，独立于 体内存在的潜在混杂变量，如局部和 全身激素和血液动力学。 此外，我将使用共焦 显微镜来评估两个潜在的细胞内 介质的渗透性，细胞内钙流和聚合 在薄的肾小球系膜和上皮细胞中的肌动蛋白细胞骨架 完整的活体肾小球的光学横截面。 具体而言，我将讨论以下问题： I.血管紧张素II和IGF-1，影响肾小球的全身因素， 功能，对肾小球通透性屏障有直接影响吗？ II.细胞内钙离子和肌动蛋白细胞骨架是否调节肾小球 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?