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.

项目摘要/摘要美国约有3400万人患有糖尿病。一些早期糖尿病并发症是肾小球过滤和肥大。尽管暂时增加在肾功能中，超滤光导致对肾小球滤过屏障（GFB）的不可逆转损害和肾单位。过滤是心力衰竭的次要作用之一，可以是促进性心力衰竭的原因。能够停止肾小球过滤的进展可能有助于阻止糖尿病肾脏疾病和充血性心力衰竭的发展。因此，我们寻求在肾小球滤过屏障的芯片模型上开发生理器官，以帮助研究过滤的进展。该模型将有助于促进对细胞变化的理解组成肾小球滤过屏障的内皮细胞和足细胞。为了模仿GFB，我们有共同多孔胶原膜支架相对侧的培养的足细胞和内皮细胞。这膜可以在芯片设备上移植到我们的器官中，并且可以在基础上运行培养基，膜的顶侧在两个单独的通道中。我们的模型可以有效地概括两种过滤，渗透和静液压的原因。我们的压力控制系统使我们能够控制整个GFB的静水压力，专门调节顶端和基础的压力文化室。培养基蛋白浓度的改变允许渗透控制。造型过滤将使我们能够证明细胞骨架变化，细胞 - 胶质细胞基底的上调膜附着蛋白发生在足细胞和内皮细胞中。此外，我们将显示高峰过滤将导致GFB中的膜蛋白的疤痕和堆积，这将导致在人过滤进程中看到的过滤减少。