Plasminogen in glomerular disease progression

项目摘要 影响肾小球足细胞的原发和继发性致病过程对 终末期肾病负担(ESRD)。尽管有重要证据表明足细胞是关键 肾小球细胞损伤靶点和有效治疗靶点很少，而且是商业上可用的细胞特异性 缺乏治疗。我们的长期目标是确定关键的调控途径和治疗靶点 治疗肾小球疾病。我们的工作已经确定尿丝氨酸蛋白酶纤溶酶原是一种介体。 足细胞损伤和与蛋白尿和肾功能相关的靶向生物标记物。整体而言 本应用的目的是确定纤溶酶原作为足细胞损伤的“二次打击”介质的作用和 进展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，足细胞不会暴露于纤溶酶原。在蛋白尿中 疾病，纤溶酶原通过尿激酶型纤溶酶原激活物作为 第二次出现与肾小球疾病进展风险相关的纤溶酶原尿。其基本原理是 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 进展可将其定义为治疗蛋白尿肾病的靶向生物标记物。我们的 假设将通过追求两个具体目标来检验：目标1将确定纤溶酶原在足细胞中的作用 损伤和肾小球疾病。我们将确定纤溶酶原诱导足细胞损伤的机制， 检测足细胞纤溶酶原激活物抑制物1在肾小球疾病进展中的作用，并利用 CureGN队列研究确定尿纤溶酶原与人类肾小球疾病的关系 进步。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。 使用遗传模型以及针对纤溶酶原激活的新型药理化合物。我们的 创新的方法利用最先进的细胞和分子生物学、生物标记物分析、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中介。 这些贡献意义重大，因为它们是有望推进的研究连续体的一部分。 了解肾小球疾病的进展，并确定治疗目标和改进策略 临床结果。

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.