suPAR and renal fibrosis

suPAR与肾纤维化

基本信息

批准号：
10220027
负责人：
Jochen Reiser
金额：
$ 45.04万
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 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10220027
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.

抽象的慢性肾病 (CKD) 是死亡率的主要原因，也是医疗保健面临的财务挑战在美国，治疗选择稀缺、间接且不充分，而 CKD 正在日益发展。我们这个时代最大的未满足的医疗需求之一。一旦肾脏受损，疾病的进展取决于纤维化的程度，我们和其他人进行了独特的观察，认为可溶性可能因患者而异。尿激酶纤溶酶原激活剂受体 (uPAR) 的形式是发生和流行的危险因素 suPAR 是一种由 CKD 产生的三指毒素。骨髓中的未成熟骨髓细胞和血浆中的检修以调节整合素功能肾脏中 suPAR 水平升高或某些 suPAR 亚型的存在是因果关系。通过介导肾小球足细胞和近端肾小管细胞的损伤参与 CKD 与 β 整合素的特异性相互作用基于我们已发表的新颖的初步观察结果。 suPAR 介导的整合素激活驱动肾脏纤维化程序，我们计划进行研究 suPAR 与不同肾单位片段中不同 β 整合素相互作用的后果以及探索其在促进肾小球和肾小管间质纤维化中的作用三个独立的目标。正在提议：首先，我们将确定翻译 suPAR-αvβ3 的分子机制使用表面等离子体共振将整合素信号传递至足细胞损伤和肾小球硬化其次，我们将确定实验、培养细胞实验和 suPAR 转基因小鼠模型。肾小管损伤中驱动 suPAR-αvβ6 整合素信号传导的分子机制通过基因修饰肾小管整合素功能来治疗肾小管间质纤维化。研究使用基于肽的 uPAR 阻断策略及其治疗方式该提案中概述的实验将使我们能够分离不同的纤维化途径。肾纤维化的 suPAR 级联中的步骤并确定最佳干预方案因此，见解。这笔赠款将为打击 suPAR 介导的预防和治疗策略提供基础纤维化和 CKD。