PHYSICO-CHEMICAL ASPECTS OF RENAL TRANSPORT PROCESSES

正常的肾小球毛细血管壁对水具有极强的渗透性，但在防止血浆蛋白损失进入肾小球超滤液方面非常有效。在肾脏疾病的主要形式中，肾小球功能的这两个方面往往受损：水过滤能力降低，伴随着选择性保留血浆中大分子的能力降低。肾小球通透性正常或受损的结构基础仍然知之甚少。拟议的研究的总体目标是开发理论模型，将这些功能特性的物理特性的结构，包括毛细血管壁，其中包括有孔内皮细胞，肾小球基底膜（GBM），和上皮细胞过滤狭缝与狭缝隔膜。一个具体的目标是表征水和大分子在新型琼脂糖-葡聚糖凝胶中的运动，该凝胶被设计为GBM的实验模型。第二个目标，也涉及跨GBM的运输，是发展一种理论来预测丰富的溶质（如主要的血浆蛋白）对不同大小的示踪剂通过凝胶或纤维膜的运动的影响。来自GBM样材料的这些研究的结果，连同大分子穿过屏障的细胞部分的运动的改进的流体动力学描述，导致第三个目标，其是更准确地模拟水和不带电的大分子在肾小球中作为一个整体的过滤。其他目的是应用基于结构的流体动力学模型在人类肾小球疾病的合作研究，并扩展它们来描述肾小球内的信号转导事件，涉及肾小球上皮和内皮细胞之间的大分子运动。

The normal glomerular capillary wall is extremely permeable to water, and yet very effective at preventing the loss of plasma proteins into the glomerular ultrafiltrate. In the principal forms of kidney disease both of these aspects of glomerular function tend to be impaired: there is a reduced capacity for filtration of water, accompanied by less ability to selectively retain large molecules in plasma. The structural basis for normal or impaired glomerular permeability properties remains poorly understood. The overall objective of the proposed research is to develop theoretical models which will relate these functional properties to the physical characteristics of the structures that comprise the capillary wall, which include the fenestrated endothelium, glomerular basement membrane (GBM), and epithelial filtration slits with slit diaphragms. One specific aim is to characterize the movement of water and macromolecules across novel agarose-dextran gels that are designed as experimental models for the GBM. A second aim, also related to transport across the GBM, is to develop a theory to predict the effects of abundant solutes (such as the major plasma proteins) on the movement of tracers of varying size through gels or fibrous membranes. The results from these studies of GBM-like materials, together with improved hydrodynamic descriptions of macromolecule movement across the cellular parts of the barrier, lead to a third objective, which is to more accurately simulate filtration of water and uncharged macromolecules in the glomerulus as a whole. Additional aims are to apply the structure-based hydrodynamic models in collaborative studies of human glomerulopathies, and to extend them to describe intraglomerular signalling events that involve the movement of macromolecules between the glomerular epithelium and endothelium.