A theory of filtration and transport within the mesangium

系膜内的过滤和运输理论

• 批准号: 8785911
• 负责人: Sarah Elizabeth Hunt
• 金额: $ 2.67万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-25 至 2016-08-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8785911
• 关键词: Affect; Attention; Basement membrane; Biological; Biological feedback; Blood capillaries; Cells; Chemicals; Chronic Kidney Failure; Collecting Tube; Computer Simulation; Contracts; Cost of Illness; Dependence; Development; Disease; Disease Progression; Elements; End stage renal failure; Endothelium; Environment; Equation; Event; Fibrosis; Filtration; Finite Element Analysis; Glomerular Capillary; Goals; Hypertrophy; Immunoglobulin A; Individual; Kidney; Kidney Diseases; Laws; Ligands; Liquid substance; Mechanics; Modeling; Outcome; Patients; Permeability; Physiological; Plasma; Play; Population; Process; Public Health; Publishing; Reaction; Relative (related person); Renal glomerular disease; Role; Shapes; Signal Transduction; Simulate; Solutions; Stress; Stretching; Structure of glomerular mesangium; Symptoms; Testing; Theoretical model; Thick; Time; Tissues; Tracer; Work; base; capillary; fluid flow; glycosylation; improved; irritation; kidney vascular structure; macromolecule; mesangial cell; podocyte; pressure; public health relevance; receptor; response; simulation; theories

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.

描述(申请人提供)：慢性肾脏疾病(CKD)影响14%的美国人口。慢性肾脏病通常包括肾滤过单位和肾小球的损害，这种损害通常包括肾小球系膜的变化。众所周知，系膜细胞对其直接环境做出反应，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。这项拟议研究的目标是建立一个跨系膜的流体和物种运输的理论模型。在Deen和他的同事为肾小球毛细血管过滤建立的传统基础上，我建议建立一个通过系膜的跨壁过滤模型。我将模拟系膜中的血浆流动和大分子运输，将这个模型应用于IgA肾病的特定病例，建立系膜应力和应变的模型，并通过允许系膜细胞在拉伸时收缩来纳入生物反馈。我将使用达西定律描述肾小球系膜基质中的流动，并以斯托克斯流动的形式描述其在相邻肾小球毛细血管中的流动。我将使用有限元分析来求解该模型 方程在单个毛细管中，理想化为直管，与其相关的系膜，理想化为薄板。系膜细胞也将被模拟为矩形小体，占据系膜的中央部分。这项工作的结果不仅将提供一种物理上的 了解系膜转运和过滤的基础，也是量化相对 不同参数对系膜累积的贡献。它将揭示反常的作用 免疫球蛋白糖基化，系膜细胞受体的改变，以及导致大分子堆积的过滤部分。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，改善公共健康。