suPAR and renal fibrosis

suPAR与肾纤维化

基本信息

批准号：
10035085
负责人：
Jochen Reiser
金额：
$ 45.91万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-20 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10035085
关键词：
Affect Affinity Animal Model Binding Proteins Biological Assay Blood Bone Marrow CD44 gene CRISPR/Cas technology Cell physiology Cells Cellular Structures Chronic Kidney Failure Clinical Cultured Cells Development Disease Disease Progression Epithelial Cells Event Exhibits Family Fibrosis Fingers Focal Segmental Glomerulosclerosis Grant HK2 gene Health Healthcare In Vitro Incidence Individual Infusion procedures Injury Innate Immune Response Integrin alphaV Integrin alphaVbeta3 Integrin beta Chains Integrins Kidney Kidney Diseases Kidney Failure Knock-out Knockout Mice Measures Mediating Medical Modality Modeling Molecular Myeloid Cells Nephrons Neurotoxins Participant Pathway interactions Patients Pattern Peptides Plasma Play Prevention strategy Protein Isoforms Proteins Publishing Recurrence Reporting Risk Factors Role Signal Transduction Signaling Protein Stream Surface Plasmon Resonance TGFBI gene Testing Therapeutic Time Toxin Transgenic Mice Translating Tubular formation United States Ureteral obstruction Urokinase Plasminogen Activator Receptor base cell injury cohort combat effective therapy experimental study glomerulosclerosis in vivo injured insight integrin beta6 interstitial kidney fibrosis member mortality mouse model novel novel therapeutics overexpression periostin podocyte post-transplant prevent programs protein protein interaction treatment strategy

项目摘要

Abstract Chronic kidney disease (CKD) is a major driver of mortality and a financial challenge for healthcare in the United States. Treatment options are scarce, indirect and not sufficient, whilst CKD is growing into one of the largest unmet medical needs of our time. Once the kidney is injured, progression of the disease is dependent on the degree of fibrosis, which can differ from patient to patient. We and others have made the unique observation that the soluble form of urokinase plasminogen activator receptor (uPAR) is a risk factor for incident and prevalent kidney diseases across the spectrum of CKD. suPAR is a three finger toxin that is produced by immature myeloid cells in the bone marrow and circulates in the plasma to regulate integrin function in the kidney. Elevated suPAR levels or the presence of certain suPAR isoforms are causally involved in CKD by mediating injury to both glomerular podocytes and proximal tubular cells through specific interactions with β integrins. Building on our published and novel preliminary observations that suPAR-mediated integrin activation drives fibrotic programs in the kidney, we plan to investigate the consequences of suPAR interactions with distinct β integrins in different nephron segments and explore its role in promoting both glomerular and tubulointerstitial fibrosis. Three independent aims are being proposed: First, we will determine the molecular mechanisms that translate suPAR-αvβ3 integrin signaling into podocyte injuries and glomerular sclerosis using surface plasmon resonance assays, cultured cell experiments and suPAR transgenic mouse models. Second, we will determine the molecular mechanisms that drive suPAR-αvβ6 integrin signaling in tubular injuries and tubulointerstitial fibrosis by genetically modifying the tubular integrin function. Third, we will investigate therapeutic modalities using peptide based blocking strategies for uPAR and its associated fibrotic pathways. Experiments outlined in this proposal will allow us to separate different steps in the suPAR cascade of kidney fibrosis and define best options to intervene. As such, insights from this grant will provide a basis for preventive and treatment strategies to combat suPAR mediated fibrosis and CKD.

抽象的慢性肾脏病（CKD）是死亡率和医疗保健财务挑战的主要驱动力美国。我们这个时代最大的未满足医疗需求之一。一旦肾脏受伤，该疾病的进展取决于纤维化的degeree 我们和其他人都可以不同。尿激酶纤溶酶原活化剂受体（UPAR）的形式是出现和普遍的危险因素 CKD频谱中的肾脏疾病。骨髓中的未成熟髓样细胞并在血浆中循环以调节整联蛋白功能在肾脏中。通过介导肾小球足细胞和近端管状细胞的损伤参与CKD 与整合素的特定互动。 Supar介导的整联蛋白激活驱动肾脏中的纤维化程序，我们计划调查在不同的肾单段中与不同的β整合蛋白的Supar相互作用的后果和探索其在促进肾小球和肾小管间隙纤维化方面的作用。正在提出：首先，我们将确定翻译supar-αvβ3的分子机制整合素信号传导到足细胞损伤和肾小球扇形中，使用表面等离子体共振屁股，培养的细胞实验和Supar转基因小鼠模型在管状损伤和通过基因修饰管状整联蛋白功能，我们会的使用基于肽的UPAR和ATS的基于肽的阻塞策略调查治疗方式相关的纤维化途径。肾脏纤维化级联的步骤，定义了这样的最佳选择从这笔赠款中，将提供预防和治疗策略以对抗Supar中介的基础纤维和CKD。