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（由申请人提供）：慢性肾病 (CKD) 影响着 14% 的美国人口。 CKD 通常包括肾脏过滤单位肾小球的损伤，而这种损伤通常包括肾小球系膜的变化。众所周知，系膜细胞会对周围环境做出反应，包括化学和物理信号。目前我们对系膜微环境的了解还不完整。拟议研究的目标是建立整个系膜中流体和物质运输的理论模型。基于 Deen 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。我将模拟系膜中的血浆流动和大分子运输，将该模型应用于 IgA 肾病的具体病例，建立系膜中的应力和应变模型，并通过允许系膜细胞响应拉伸而收缩来纳入生物反馈。我将使用达西定律描述通过系膜基质的流动，并将相邻肾小球毛细血管中的流动描述为斯托克斯流。我将使用有限元分析来求解模型 单个毛细管（理想化为直管）及其相关的系膜（理想化为薄板）中的方程。系膜细胞也将被建模为矩形体，占据系膜的中央部分。这项工作的结果不仅会提供物理上的 理解系膜运输和过滤的基础，也是量化相对值的一种方法 不同参数对系膜积累的贡献。它将揭示异常的角色 IgA 糖基化、系膜细胞受体的改变以及导致大分子积累的过滤分数。这些结果将量化所提出的疾病机制的影响，这可能会提出新的治疗方案，改善公众健康。