Plasminogen in glomerular disease progression

肾小球疾病进展中的纤溶酶原

• 批准号: 10183244
• 负责人: Kirk N Campbell
• 金额: $ 53.84万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10183244
• 关键词: Actins; Affect; Albuminuria; Amiloride; Biological Markers; CD36 gene; Cells; Cellular biology; Clinical; Data; Development; Disease; Disease Progression; Diuretics; Edema; End stage renal failure; Focal Adhesions; Focal Segmental Glomerulosclerosis; Generations; Genetic Models; Goals; HIV; Human; Impairment; Injury; Kidney Diseases; Knowledge; Mediating; Mediator of activation protein; Modeling; Molecular Biology; NADPH Oxidase; Nonesterified Fatty Acids; Outcome; Pathogenesis; Pathogenicity; Patients; Pharmaceutical Chemistry; Pharmacology; Phosphotyrosine; Plasmin; Plasminogen; Plasminogen Activator Inhibitor 1; Process; Production; Property; Puromycin Aminonucleoside; Rattus; Reactive Oxygen Species; Regulation; Regulatory Pathway; Renal function; Renal glomerular disease; Research; Risk; Role; Serine Protease; Signal Transduction; Superoxides; Systems Biology; Testing; Therapeutic; Therapeutic Agents; Time; Up-Regulation; Urokinase; Urokinase Plasminogen Activator Receptor; Work; base; cell motility; cohort; efficacy testing; glomerular filtration; imaging system; improved; innovation; kidney biopsy; mouse model; nanomolar; novel; novel therapeutics; oxidized low density lipoprotein; plasminogen receptor; podocyte; scavenger receptor; targeted biomarker; therapeutic target; tool; trypsin-like serine protease; uptake; urinary

Project Summary Primary and secondary pathogenic processes affecting glomerular podocytes contribute significantly to the burden of end-stage renal disease (ESRD). Despite significant evidence identifying the podocyte as the key glomerular cell target for injury, validated therapeutic targets are scarce and commercially available cell-specific therapy is lacking. Our long-term goal is to identify key regulatory pathways and therapeutic targets in the treatment of glomerular disease. Our work has identified the urinary serine protease plasminogen as a mediator of podocyte injury and a targetable biomarker that correlates with albuminuria and renal function. The overall objective of this application is to define the role of plasminogen as a “second hit” mediator of podocyte injury and a potential therapeutic target in progressive glomerular disease. Our central hypothesis is that under normal conditions with an intact glomerular filtration barrier, podocytes are not exposed to plasminogen. In proteinuric disease, plasminogen enhances podocyte injury through urokinase type plasminogen activator as part of a second hit with plasminogenuria correlating with the risk of glomerular disease progression . The rationale for the proposed research is that characterizing the role of plasminogen in podocyte injury and glomerular disease progression could define it as a targetable biomarker in the treatment of proteinuric kidney disease. Our hypothesis will be tested by pursuing two specific aims: Aim 1 will define the role of plasminogen in podocyte injury and glomerular disease. We will define the mechanism by which plasminogen induces podocyte injury, test the role of podocyte plasminogen activator inhibitor 1 in glomerular disease progression and leverage the CureGN cohort to define the relationship between urinary plasminogen and human glomerular disease progression. In Aim 2 we will test plasminogen inhibition as a therapeutic strategy in proteinuric kidney disease using genetic models as well as novel pharmacologic compounds targeting plasminogen activation. Our innovative approach utilizes state of the art cell and molecular biology, biomarker analysis, imaging, systems biology and medicinal chemistry tools to define plasminogen as a mediator of glomerular disease progression. These contributions are significant because they are part of a continuum of research that is expected to advance understanding of glomerular disease progression and identify therapeutic targets and strategies to improve clinical outcomes.

项目概要 影响肾小球足细胞的原发性和继发性致病过程对 尽管有大量证据表明足细胞是终末期肾病（ESRD）的负担。 肾小球细胞损伤靶标，经过验证的治疗靶标稀缺且商业上可用的细胞特异性 我们的长期目标是确定关键的调控途径和治疗靶点。 我们的工作已确定尿丝氨酸蛋白酶纤溶酶原作为介质。 足细胞损伤和与蛋白尿和肾功能相关的靶向生物标志物。 本申请的目的是确定纤溶酶原作为足细胞损伤的“二次打击”介质的作用，以及 进行性肾小球疾病的潜在治疗靶点我们的中心假设是在正常情况下。 在肾小球滤过屏障完整的情况下，足细胞不会暴露于蛋白尿中的纤溶酶原。 在疾病中，纤溶酶原通过尿激酶型纤溶酶原激活剂增强足细胞损伤，作为 第二个打击与肾小球疾病进展风险相关的纤溶酶原尿。 拟议的研究是表征纤溶酶原在足细胞损伤和肾小球疾病中的作用 可以将其定义为治疗蛋白尿肾病的靶向进展生物标志物。 将通过追求两个具体目标来检验假设： 目标 1 将定义纤溶酶原在足细胞中的作用 我们将定义纤溶酶原诱导足细胞损伤的机制， 测试足细胞纤溶酶原激活剂抑制剂 1 在肾小球疾病进展中的作用并利用 CureGN 队列定义尿纤溶酶原与人类肾小球疾病之间的关系 在目标 2 中，我们将测试纤溶酶原抑制作为蛋白尿肾病的治疗策略 使用遗传模型以及新型药理学靶向化合物纤溶酶原激活。 创新方法利用最先进的细胞和分子生物学、生物标志物分析、成像、系统 生物学和药物化学工具将纤溶酶原定义为肾小球疾病进展的介质。 这些贡献意义重大，因为它们是预计将推进的连续研究的一部分 了解肾小球疾病进展并确定治疗目标和改善策略 临床结果。