Mechanisms involved in podocyte damage in Alport Syndrome

阿尔波特综合征足细胞损伤的机制

基本信息

批准号：
10503338
负责人：
Stefano Da Sacco
金额：
$ 69.74万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
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：
2022-08-15 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10503338
关键词：
Affect Amniotic Fluid Binding Biology Cell Cycle Cell Cycle Progression Cell Cycle Stage Cell Survival Cell physiology Cells Chronic Kidney Failure Data Deposition Deterioration Development Disease Progression End stage renal failure Endothelial Cells Etiology Evaluation Event Experimental Models Fluorescence Foundations Functional disorder Genes Goals Hereditary nephritis Human In Vitro Injury Injury to Kidney Integrin alphaVbeta3 Kidney Kidney Diseases Knowledge Lead Maintenance Methods Micelles Modeling Molecular Morphology Mus Pathway interactions Patients Phase Regulation Renal function Renal glomerular disease Research Role Scheme Series Signal Transduction Structure System Technology Testing Therapeutic Therapeutic Agents Therapeutic Effect Transgenic Organisms Ubiquitination Up-Regulation Vascular Endothelial Growth Factors WT1 gene Work base cell injury delivery vehicle design glomerular basement membrane glomerular endothelium glomerular filtration glomerular function in vivo inhibitor inhibitor therapy innovation insight knock-down mouse model nanoparticle novel novel therapeutics osteopontin peptide amphiphiles podocyte prevent progenitor programs repaired standard of care targeted delivery therapeutic target

项目摘要

During the progression of most chronic kidney diseases (CKD) podocytes are lost, and injury to glomerular endothelial cells, and changes in the composition of the glomerular basement membrane (GBM) lead to alterations of the structure and function of the glomerular filtration barrier. Understanding the mechanisms that induce glomerular cell damage could possibly pave the way to the discovery of new pathways that can be targeted to slow kidney disease progression or possibly reverse it. Data presented in this proposal, using the glomerulus on a chip platform and the FUCCI mouse model that allows tracking of the cell cycle changes in vivo, show that podocytes present an altered binding to their GBM, they exit their quiescent state, and are lost during disease progression in Alport Syndrome (AS) mice, our model of CKD characterized by a defective GBM. We have evidence that miR-193a is upregulated specifically in mouse and human AS podocytes and that its inhibition favors podocyte survival and modulate podocyte interactions with their GBM. Based on our data, we hypothesize that re-establishing glomerular function by modulating important molecular pathways that are responsible for podocyte survival prevents further injury, thus slowing kidney disease progression. Using multiple transgenic AS FUCCI mice and in vitro human systems, we will study the molecular mechanisms that regulate the podocyte cell cycle and their interaction with a defective GBM, typical of AS. Specifically, in Aim 1 we will study in vitro how modulation of miR-193a can “re-program” cellular signaling networks that influence podocyte biology. In Aim 2 we will perform in vivo studies to determine the therapeutic effect of miR-193a inhibitor delivered as cargo of an innovative delivery vehicle based on peptide amphiphile micelle nanoparticles specifically designed to target podocytes in our AS colonies. Successful completion of this proposal will provide novel insights into key factors critical for maintenance of glomerular structure and function. Importantly, this knowledge would likely be applicable to other forms of CKD and possibly facilitate the discovery of new therapeutic agents tailored specifically to sustain podocyte survival and minimize glomerular damage.

在大多数慢性肾脏疾病（CKD）足细胞的进展过程中，肾小球受伤内皮细胞，以及肾小球基底仪（GBM）组成的变化导致肾小球滤过屏障的结构和功能的改变。诱导肾小球细胞损伤可能会付出的可能性，以发现发现的新途径可以针对肾脏疾病进展缓慢或可能将其逆转。在本提案中介绍的数据，使用芯片平台上的glomerulus和fucci Mousel的数据体内周期变化的跟踪，表明足细胞对其GBM的结合发生了变化，它们退出它们的静态状态，在疾病进展过程中丢失了Alport综合征（AS）小鼠，我们的CKD模型以Decective GBM为特征。人作为足细胞，这是抑制剂有利于足细胞的生存和模块化相互作用他们的GBM。负责足细胞存活的重要分子途径可防止进一步的损伤放缓肾脏疾病的进展。使用多个转基因作为Fucci小鼠和体外人类系统，我们将研究分子机制调节足细胞周期及其与典型AS的缺陷GBM的相互作用。 1我们将在体外研究miR-193a的调节如何可以影响影响的细胞信号网络 AIM 2中的Podocyte生物学。我们将进行体内研究作为基于肽两亲的胶束纳米颗粒的货运动物的货物交付专门针对我们的殖民地的目标。对维持肾小球结构和功能的关键因素的新颖洞察力知识可能专门为维持足细胞存活而量身定制的治疗剂，并最大程度地减少肾小球损伤。