权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Thrombin-Mediated Podocyte Injury Mechanisms

凝血酶介导的足细胞损伤机制

基本信息

批准号：
10366953
负责人：
Bryce Andrew Kerlin
金额：
$ 46.81万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-22 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10366953
关键词：
Acute Address Animal Model Anticoagulant therapy Anticoagulants Binding Proteins Biology Bioluminescence Blood Coagulation Factor Blood coagulation Cause of Death Cell Line Chronic Kidney Failure Coagulation Process Complement Data Development Disease Progression End stage renal failure Energy Transfer Enzyme Precursors FDA approved Factor X Flow Cytometry Fluorescence Functional disorder Generations Genetic Glomerular Filtration Rate Goals Half-Life Health Hematological Disease In Situ Injury Interruption Kidney Knock-out Knockout Mice Lead Mediating Medical Research Messenger RNA Methods Mission Modeling Molecular Molecular Biology Molecular Target Mus Mutagenesis National Institute of Diabetes and Digestive and Kidney Diseases Nephrotic Syndrome Oral Outcome Pathway interactions Peptide Hydrolases Pharmacology Plasma Positioning Attribute Proteinase-Activated Receptors Proteins Proteinuria Prothrombin Public Health Publishing Quality of life Rattus Reagent Receptor Signaling Research Research Priority Research Project Grants Role Signal Pathway System Techniques Testing Thrombin Thromboplastin United States United States Food and Drug Administration base conditional knockout design drug clearance effective therapy efficacy evaluation improved inhibitor/antagonist innovation kidney cell knock-down nanoparticle new therapeutic target novel novel strategies novel therapeutics overexpression podocyte prevent side effect

项目摘要

PROJECT SUMMARY/ABSTRACT Nephrotic syndrome is a leading cause of end stage kidney disease, which is the eighth leading cause of death in the United States. Thrombin injures podocytes and its inhibition reduces nephrotic-range proteinuria and podocyte injury, two key drivers of nephrotic syndrome progression toward end stage kidney disease. Thus, there is a critical need to discern the molecular mechanisms underlying thrombin-mediated podocyte injury without which, the development of targeted, safe, and effective therapies that slow or halt nephrotic syndrome progression is likely to remain limited. The overall objective of this proposal is to define molecular mechanisms underlying thrombin-dependent, protease-activated receptor-mediated podocyte injury and determine if inhibition of this signaling pathway reduces progression toward end stage kidney disease. The central hypothesis is that thrombin-mediated protease-activated receptor signaling is a modifiable driver of RhoA-dependent podocyte injury during nephrotic syndrome progression. This project will integrate methods from the podocyte and coagulation biology fields including: mouse and rat nephrotic syndrome models, coagulation factor knockdown and conditional protease-activated receptor knockout mice, innovative nanoparticle-mRNA overexpression of coagulation factors, repurposing of Food and Drug Administration approved direct oral anticoagulants to mitigate podocyte injury, a novel flow cytometry approach to quantitate podocyte injury, and molecular biology methods including bimolecular fluorescence complementation and bioluminescence resonance energy transfer in genetically modified podocyte cultures. These complementary methods will be used to investigate the pathophysiologic role of thrombin in podocyte injury and nephrotic syndrome progression toward end stage kidney disease. Our Aims are designed to (1) Reveal the prothrombinase that produces intraglomerular, podocytopathic thrombin to drive podocyte injury and nephrotic syndrome progression, (2) Test the ability of direct oral anticoagulant therapy as a novel method to reduce nephrotic syndrome progression, and (3) Discover the molecular mechanisms by which thrombin-mediated protease-activated receptor signaling stimulates RhoA- dependent podocyte injury. This project is directly responsive to the mission of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) which is to “…support medical research…on kidney…and hematologic diseases, to improve people’s health and quality of life.” In addition, this project directly addresses important research priorities described in the Kidney Research National Dialogue and key aspects of the Healthy People 2030 Chronic Kidney Disease objectives. Completion of the proposed project is expected to establish the mechanisms underlying thrombin-mediated podocyte injury and enable exploitation of existing, Food and Drug Administration approved, direct oral anticoagulants as novel therapeutics to slow or halt NS progression.

项目总结/摘要肾病综合征是导致终末期肾病的主要原因，也是导致死亡的第八大原因在美国凝血酶损伤足细胞，其抑制作用可减少肾病范围的蛋白尿，足细胞损伤，肾病综合征进展为终末期肾病的两个关键驱动因素。因此，本发明的目的是，迫切需要了解凝血酶介导的足细胞损伤的分子机制如果没有这些，发展有针对性的，安全的，有效的治疗，减缓或停止肾病综合征进展可能仍然有限。本提案的总体目标是确定分子机制潜在的凝血酶依赖性，蛋白酶激活受体介导的足细胞损伤，并确定是否抑制这一信号通路的减少进展到终末期肾病。核心假设是，凝血酶介导的蛋白酶激活受体信号是RhoA依赖性足细胞的可修饰驱动因子肾病综合征进展过程中的损伤。该项目将整合来自足细胞的方法，凝血生物学领域包括：小鼠和大鼠肾病综合征模型，凝血因子敲低和条件性蛋白酶激活受体敲除小鼠，创新的纳米颗粒-mRNA过表达，凝血因子，重新利用食品和药物管理局批准的直接口服抗凝剂，以减轻足细胞损伤，定量足细胞损伤的新流式细胞术方法和分子生物学方法包括双分子荧光互补和生物发光共振能量转移，遗传修饰的足细胞培养物。这些补充方法将用于调查凝血酶在足细胞损伤和肾病综合征向终末期进展中的病理生理作用肾病我们的目的是（1）揭示凝血酶原酶产生肾小球内，足细胞病变凝血酶驱动足细胞损伤和肾病综合征进展，（2）测试直接口服抗凝治疗作为一种新的方法，以减少肾病综合征的进展，和（3）发现凝血酶介导的蛋白酶激活受体信号刺激RhoA的分子机制，依赖性足细胞损伤该项目直接响应国家糖尿病研究所的使命和消化和肾脏疾病（NIDDK），其目的是“. 血液病，以改善人们的健康和生活质量。”此外，该项目还直接针对肾脏研究全国对话中描述的重要研究优先事项和健康 2030年慢性肾脏病目标。拟议项目完成后，凝血酶介导的足细胞损伤的潜在机制，并使现有的，食物和药物管理局批准，直接口服抗凝剂作为新的治疗方法，以减缓或停止NS进展。