Glomerulus on a Chip: A Model to Study Glomerular Hyperfiltration

芯片上的肾小球：研究肾小球超滤的模型

• 批准号: 10707892
• 负责人: Charles Garcia Alver
• 金额: $ 5.27万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-06 至 2026-09-05
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707892
• 关键词: Address; Animal Model; Apical; Basement membrane; Biological Phenomena; Biomedical Engineering; Biomimetics; Caring; Cell Culture Techniques; Cells; Chronic Kidney Failure; Cicatrix; Coculture Techniques; Collagen; Complications of Diabetes Mellitus; Congestive Heart Failure; Consumption; Culture Media; Cytoskeleton; Development; Devices; Diabetes Mellitus; Diabetic Nephropathy; Dialysis procedure; Disease; Disease model; Doctor of Philosophy; Endothelial Cells; Filtration; Gelatin; Generations; Glomerular Filtration Rate; Health; Heart Diseases; Heart failure; Hereditary nephritis; Human; Hydrogels; Hydrostatic Pressure; Hypertrophy; In Vitro; Kidney; Kidney Diseases; Kidney Failure; Kidney Transplantation; Knowledge; Left; Liquid substance; Medicare; Membrane; Membrane Proteins; Mentors; Metabolic; Microfluidic Microchips; Modeling; Nephrons; Osmolar Concentration; Osmosis; Osmotic Pressure; Pathogenesis; Pathologic; Patients; Persons; Physiological; Plasma; Porosity; Proteins; Renal function; Running; Scientist; Side; System; Therapeutic Studies; Therapeutic Uses; Training; Transplantation; United States; Up-Regulation; arteriole; body system; combat; constriction; cost; experimental study; extracellular; glomerular basement membrane; glomerular filtration; hemodynamics; improved; in vitro Model; mimetics; new technology; novel; organ on a chip; podocyte; pressure; renal damage; response; scaffold; skills; stem; tool

Project Summary/Abstract Approximately 34 million people in the United States suffer from Diabetes Mellitus. Some of the early complications of diabetes are glomerular hyperfiltration and hypertrophy. Despite being a temporary increase in kidney function, hyperfiltration progresses into irreversible damage to the glomerular filtration barrier (GFB) and nephron. Hyperfiltration is additionally one of the secondary effects of heart failure and can be a precipitating cause of progressive heart failure. Being able to stop the progression of glomerular hyperfiltration may help stem the development of diabetic kidney disease and congestive heart failure. As such, we seek to develop a physiomimetic Organ on a Chip model of the glomerular filtration barrier to aid in studying the progression of hyperfiltration. This model will help to facilitate an understanding of the cellular changes to the endothelial cells and podocytes that make up the glomerular filtration barrier. To mimic the GFB, we have co- cultured podocytes and endothelial cells on opposite sides of a porous collagen membrane scaffold. The membrane can be transplanted into our Organ on a Chip device, and media can be run across the basal and apical sides of the membrane in two separate channels. Our model can effectively recapitulate the effects of both causes of hyperfiltration, osmotic and hydrostatic. Our pressure control system on the chip allows us to control the hydrostatic pressure across our GFB, specifically adjusting the pressure in the apical and basal culture chambers. Alteration of the media protein concentrations allows for osmotic control. Modeling hyperfiltration will allow us to demonstrate the cytoskeletal changes, upregulation of cell-glomerular basement membrane attachment proteins, that occur in the podocytes and endothelial cells. Additionally, we will show that peak hyperfiltration will lead to scarring and buildup of membrane proteins in the GFB that will lead to decreased filtration as is seen in human hyperfiltration progression.

项目概要/摘要 美国大约有 3400 万人患有糖尿病。一些早期的 糖尿病的并发症是肾小球过度滤过和肥大。尽管是暂时的增加 在肾功能中，过度滤过会对肾小球滤过屏障 (GFB) 造成不可逆的损害 和肾单位。过度滤过也是心力衰竭的继发效应之一，可能是 诱发进行性心力衰竭的原因。能够阻止肾小球过度滤过的进展 可能有助于阻止糖尿病肾病和充血性心力衰竭的发展。因此，我们力求 开发肾小球滤过屏障的拟体器官芯片模型，以帮助研究 过度滤过的进展。该模型将有助于促进对细胞变化的理解 构成肾小球滤过屏障的内皮细胞和足细胞。为了模仿 GFB，我们有 co- 在多孔胶原膜支架的相对侧培养足细胞和内皮细胞。这 膜可以移植到我们的芯片设备上的器官中，并且培养基可以穿过基底和 膜的顶端位于两个独立的通道中。我们的模型可以有效地概括以下因素的影响 超滤的两个原因是渗透性和静水压。我们的芯片压力控制系统使我们能够 控制 GFB 的静水压力，特别是调节顶端和基底的压力 培养室。改变培养基蛋白质浓度可以实现渗透控制。造型 超滤将使我们能够展示细胞骨架的变化以及细胞肾小球基底的上调 膜附着蛋白，存在于足细胞和内皮细胞中。此外，我们还将展示 峰值超滤将导致 GFB 中膜蛋白形成疤痕和积聚，从而导致 正如人类超滤进展中所见，滤过减少。