A theory of filtration and transport within the mesangium

描述（由申请人提供）：慢性肾脏疾病（CKD）影响14%的美国人口。CKD通常包括对肾脏的过滤单位肾小球的损害，并且这种损害通常包括肾小球系膜的变化。已知肾小球系膜细胞对其直接环境作出反应，包括化学和物理信号。我们对系膜微环境的了解目前还不完全。该研究的目的是建立一个理论模型的流体和物种运输整个系膜。基于迪恩及其同事建立的肾小球毛细血管滤过的传统，我建议建立一个通过系膜的透壁滤过模型。我将模型血浆流动和大分子运输的系膜，应用该模型的伊加肾病的具体情况下，建立一个模型的应力和应变的系膜，并纳入生物反馈，允许系膜细胞收缩响应拉伸。我将用达西定律描述通过系膜基质的血流，并将邻近肾小球毛细血管中的血流描述为斯托克斯血流。我将使用有限元分析来解决这个模型 方程中的一个单一的毛细管，理想化为一个直管，其相关的系膜，理想化为一个薄板。肾小球系膜细胞也将被建模为矩形体，占据系膜的中心部分。这项工作的结果将不仅提供一个物理 了解系膜运输和过滤的基础，也是一种量化相对 不同参数对系膜积聚的贡献。它将揭示异常的作用 伊加糖基化、系膜细胞受体改变和滤过分数引起大分子蓄积。这些结果将量化拟议的疾病机制的影响，这可能会提出新的治疗方案，改善公众健康。

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) affects 14% of the U.S. population. CKD often includes damage to the kidney's filtration unit, the glomerulus, and such damage usually includes changes to the glomerular mesangium. Mesangial cells are known to respond to their immediate environment, including chemical and physical signals. Our understanding of the mesangial microenviroment is currently incomplete. The goal of the proposed study is to build a theoretical model of fluid and species transport throughout the mesangium. Building on the tradition established for glomerular capillary filtration by Deen and colleagues, I propose to build a model of transmural filtration through the mesangium. I will model plasma flow and macromolecular transport in the mesangium, apply this model to the specific case of IgA nephropathy, build a model of the stresses and strains in the mesangium, and incorporate biological feedback by allowing mesangial cells to contract in response to stretch. I will describe flow through the mesangial matrix using Darcy's Law, and flow in an adjacent glomerular capillary as Stokes flow. I will use finite-element analysis to solve the model equations in a single capillary, idealized as a straight tube, with its associated mesangium, idealized as a thin slab. Mesangial cells will also be modeled as rectangualr bodies, occupying the central portion of the mesangium. The results of this work will not provide not only a physical basis for understanding mesangial transport and filtration, but also a way to quantify the relative contribution of different parameters to mesangial accumulation. It will reveal the role of aberrant IgA glycosylation, alterations to mesangial cell receptors, and filtration fraction in causing macromolecular accumulation. These results will quantify the effects of proposed disease mechansims, which could suggest new treatment options, improving public health.