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

基本信息

批准号：
10464511
负责人：
Charles Garcia Alver
金额：
$ 5.18万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
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/10464511
关键词：
Address Animal Model Apical Basement membrane Biological Phenomena Biomedical Engineering Biomimetics Caring Cell Culture Techniques Cells Chronic Kidney Failure Cicatrix Collagen Complications of Diabetes Mellitus Congestive Heart Failure Consumption Culture Media 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 Osmotic Pressure Pathogenesis Pathologic Patients Persons Physiological Plasma Proteins Renal function Running Scientist Seeds Side System Therapeutic Studies Therapeutic Uses Training Transplantation United States Up-Regulation arteriole combat constriction cost experimental study extracellular glomerular basement membrane glomerular filtration hemodynamics in vitro Model mimetics new technology novel organ on a chip podocyte pressure renal damage response scaffold skills stem tool

项目摘要

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 上的静水压力，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。