STRUCTURAL DETERMINANTS OF GLOMERULAR PERMEABILITY

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最多 进行性肾脏疾病的类型，但对 肾小球通透性屏障的生理和调节不是 开发得很好，可能部分原因是缺乏模型， 肾小球功能可独立于血流动力学和 荷尔蒙因素对健康有重要作用，但不只是 水和大分子对肾小球毛细血管的渗透性 墙。 两种体外肾小球通透性模型的建立 肾小球毛细血管壁离散成分的作用 对渗透率的维持和调节可以进行分析。这个 分层的、完整的肾小球的过滤特性将在 滤过细胞同时滤过单个、完整、肾小球 毛细血管环将通过共聚焦显微镜进行检查。此外, 共聚焦显微镜有助于细胞内的研究 钙离子通量与肌动蛋白细胞骨架--血管通透性的中介 其他器官，在完整的肾小球内的离散细胞中。 这项建议旨在研究肾小球的功能。 使用这两种新技术的渗透屏障，共聚焦显微镜 和过滤单元。这些技术将被进一步描述 然后利用它来开发和扩展可用的等孔质和纤维 肾小球大分子通透性的矩阵模型。此外, 钙通量和肌动蛋白细胞骨架，可能是细胞内的介质 通透性，将在完整肾小球的离散细胞中进行检查 用共聚焦显微镜来确定它们在调节 肾小球通透性。最后，由此产生的关于 肾小球通透性将应用于两种病理生理模型 与肾小球通透性屏障的急性改变有关。

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, probably due in part to the lack of models where glomerular function can be assessed independently of the hemodynamic and hormonal factors which contribute importantly, but not solely, to the permeance of water and macromolecules across the glomerular capillary wall. The development of two in vitro models of glomerular permeability whereby the contribution of discrete components of the glomerular capillary wall to the maintenance and regulation of permeability can be analyzed. The filtration properties of layered, intact glomeruli will be assessed in a filtration cell while the filtration across single, intact, glomerular capillary loops will be examined by confocal microscopy. In addition, confocal microscopy facilitates the investigation of intracellular calcium flux and the actin cytoskeleton, mediators of permeability in other organs, in discrete cells within intact glomeruli. This proposal is designed to investigate the function of the glomerular permeability barrier with these two novel techniques, confocal microscopy and the filtration cell. The techniques will be further characterized and then utilized to develop and expand the available isoporous and fiber matrix models of glomerular macromolecule permeability. In addition, calcium flux and the actin cytoskeleton, likely intracellular mediators of permeability, will be examined in discrete cells in intact glomeruli with confocal microscopy to determine their role in the modulation of glomerular permeability. Finally, the resultant concepts about the glomerular permeability will be applied to two pathophysiologic models associated with acute alterations in the glomerular permeability barrier.