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.

项目摘要/摘要 美国约有3400万人患有糖尿病。一些早期的 糖尿病的并发症是肾小球高滤过和肥大。尽管是暂时的增加 在肾功能方面，高滤过进展为对肾小球滤过屏障(GFB)的不可逆转的损害 和尼龙。高滤过是心力衰竭的次要影响之一，可能是一种 进行性心力衰竭的诱因。能够阻止肾小球高滤过的进展 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，我们寻求 开发肾小球滤过屏障的芯片上仿生器官模型以辅助研究 高滤过的进展。这个模型将有助于理解细胞对 构成肾小球滤过屏障的内皮细胞和足细胞。为了模仿GFB，我们有联合- 在多孔胶原膜支架的两侧培养足细胞和内皮细胞。这个 膜可以在芯片设备上移植到我们的器官中，介质可以穿过基底部和 膜的顶端侧面在两个独立的通道中。我们的模型可以有效地概括 高滤过的两个原因，渗透和流体静力。我们芯片上的压力控制系统使我们能够 控制整个GFB的静液压力，特别是调整根尖和基底部的压力 文化室。改变培养基蛋白浓度可以进行渗透控制。建模 超滤将使我们能够显示细胞骨架的变化，细胞-肾小球基底物的上调 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 该峰值超滤将导致GFB中的膜蛋白结疤和积聚，这将导致 滤过率降低，就像在人类高滤过过程中看到的那样。