Development of a computational biomechanics model of the glomerulus to assess risk of mechanical stress-induced glomerular injury in conditions of reduced afferent arteriole vasoconstrictive response.

开发肾小球计算生物力学模型，以评估在传入小动脉血管收缩反应减少的情况下机械应力引起的肾小球损伤的风险。

基本信息

批准号：
9924241
负责人：
Owen Richfield
金额：
$ 2.95万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-10 至 2021-06-29
项目状态：
已结题

项目摘要

Project Summary/Abstract A reduction in the vasoconstrictive responsiveness of the afferent arteriole relative to perfusion pressure is implicated in the progression of glomerular injury in diabetes, some forms of hypertension and chronic kidney diseases involving the loss of functional nephrons. A reduction of the vasoconstrictive responsiveness of the afferent arteriole raises afferent blood flow and intraglomerular pressure which is believed to increase mechanical stress (cyclic stretch and fluid flow shear stress) on the glomerular cells. In response to cyclic stretch, mesangial cells increase deposition of extracellular matrix (ECM) components and podocytes may detach from the glomerular capillary. In response to increased shear stress, vascular endothelial cells increase production of inflammatory markers. These results collectively indicate that a reduced vasoconstrictive responsiveness of the afferent arteriole relative to perfusion pressure causes injury of glomerular cells by increasing shear stress on and cyclic stretch of the glomerular capillary walls. Although mechanical stress- induced glomerular injury is a generally accepted concept in kidney disease research, the actual magnitudes of mechanical stress, in particular shear stress and hoop stress resulting from an attenuated afferent arteriole vasoconstrictive response, are unknown. The overall aim of this proposal is to use multiscale mathematical modeling to estimate the magnitudes of shear stress and capillary wall stretch in the glomerular capillary network as a result of decreased afferent arteriole vasoconstrictive responsiveness. We will develop a “glomerular network model” that calculates flows through the capillaries of an actual, anatomically-accurate glomerular microvascular network. A feedback model of afferent arteriole resistance will be integrated with the glomerular network model to represent the complex dynamics of renal autoregulation in our model. Additionally, we will develop a computational fluid dynamics (CFD) model of a single glomerular capillary, taking into account the dynamics arising from elastic red blood cell structures flowing in a permeable channel. Taking a multiscale mathematical modeling approach, for each capillary segment of the glomerular network model, output of the glomerular network model will be mapped to parameters in the CFD capillary model to calculate shear stresses on the vessel walls. The mechanical stresses calculated using this approach will be compared to experimental parameters of previous cell studies to determine the risk of glomerular cell injury with and without the pathological hemodynamic conditions arising from reduction in afferent arteriole vasoconstrictive responsiveness. This work will serve as a basis for a glomerular injury risk index in pathological renal hemodynamic conditions and will inform the design of “glomerulus-on-a-chip” microphysiological systems. Mechanical forces are known to crucially affect the efficacy of these systems as models of disease and as drug testing platforms; thus, the proposed project will contribute to development and establishment of these systems for these contexts of use.

项目摘要/摘要相对于灌注压力，传入小动物的血管收缩反应性降低为在糖尿病中肾小球损伤的进展中实施，某些形式的高血压和慢性肾脏涉及功能肾脏丧失的疾病。减少血管收缩的反应性传入小动脉会增加传入的血液流量和磁性内压，据信它会增加肾小球细胞上的机械应力（环状拉伸和流体流动应力）。响应循环伸展，肾小球细胞会增加细胞外基质（ECM）成分和足细胞的沉积脱离肾小球毛细管。响应增加的剪切应力，血管内皮细胞增加炎症标记的产生。这些结果共同表明减少了血管收缩传入小动物相对于灌注压力的反应性会导致肾小球细胞受伤增加肾小球毛细管壁的剪切应力和循环拉伸。虽然机械应力 - 诱导肾小球损伤是肾脏疾病研究中公认的概念机械应力，尤其是由衰减的传入Artiole产生的剪切应力和箍应力血管收缩反应是未知的。该提案的总体目的是使用多尺度数学建模以估算肾小球毛细管中剪切应力和毛细管壁拉伸的尺寸网络由于减少传入小动脉血管收缩反应性。我们将发展一个 “肾小球网络模型”计算出流过实际的，解剖学精度的毛细血管肾小球微血管网络。传入小动脉抗性的反馈模型将与肾小球网络模型代表我们模型中肾脏自动调节的复杂动力学。此外，我们将开发单个肾小球毛细管的计算流体动力学（CFD）模型，考虑到在可渗透通道中流动的弹性红细胞结构引起的动力学。采用多尺度数学建模方法，适用于肾小球网络的每个毛细管段模型，肾小球网络模型的输出将映射到CFD毛细管模型中的参数计算血管壁上的剪切应力。使用这种方法计算的机械应力将是与先前细胞研究的实验参数相比，以确定肾小球细胞损伤的风险有和没有病理血流动力学条件，导致传入小动脉的减少血管收缩的响应能力。这项工作将作为肾小球伤害风险指数的基础病理肾脏血流动力学条件，将为“片段肾小球”的设计告知微生物生理系统。已知机械力完全影响这些系统的有效性疾病模型和作为药物测试平台；因此，拟议的项目将有助于发展和为这些使用环境建立这些系统。