Protein-to-Tissue Model of Glomerular Mechanobiology

该奖项的研究目标是使用不同长度尺度的计算模型来了解形成肾脏肾小球基底膜(GBM)的蛋白质的变化如何改变整个基底膜的机械性能。基底膜是肾脏过滤装置的主要结构层，因此它承受高压的能力和允许血浆通过它的能力是正常肾脏功能所必需的。从分子到组织尺度的一系列模型将被构建并链接在一起。组织的硬度和强度将根据蛋白质特性以及组织的渗透性(即其允许过滤流动的趋势)进行估计。最后，组织属性的变化，再加上已知的过滤需求，将被用来模拟GBM随着负荷或蛋白质属性的变化而发生的动态变化。如果成功，这些研究将有助于解释每天过滤40-50加仑血液的肾脏在健康条件下的表现以及在疾病中表现下降的原因。这一新的认识可能有助于推动对患有影响肾脏的遗传性疾病(例如Alport综合征)的患者以及由其他原因引起的肾脏疾病(如糖尿病)的患者进行治疗。该项目还包括培训一名生物医学工程博士生，并在梅诺明国家大学为对STEM感兴趣的学生开展一项外展计划，这将有助于增强我们高科技劳动力的实力和多样性。

The research objective of this award is to use computational models at different length scales to develop an understanding of how changes to the proteins that form the glomerular basement membrane (GBM) of the kidney alter the mechanical properties of the basement membrane as a whole. The GBM is the major structural layer of the filtration apparatus of the kidney, so its ability to withstand high pressures and allow blood plasma to pass through it is necessary for proper kidney function. A series of models from the molecular to the tissue scale will be constructed and linked together. The stiffness and strength of the tissue will be estimated based on the protein properties, as will the permeability of the tissue (i.e., its tendency to permit filtration flow through it). Finally, changes in the properties of the tissue, coupled with the known demand for filtration, will be used to model dynamic changes in the GBM in response to changes in load or protein properties.If successful, these studies will help explain how the kidney, which filters 40-50 gallons of blood every day, performs in healthy conditions and suffers decreased performance in disease. The new understanding may help drive treatments for patients with genetic diseases that affect the kidney (e.g., Alport syndrome) and also for patients with kidney disease arising from other sources, such as diabetes. The project also involves training of a Ph.D. student in biomedical engineering and an outreach program for students interested in STEM at the College of the Menominee Nation, which will contribute to the strength and diversity of our high-tech workforce.