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Plasminogen in glomerular disease progression

肾小球疾病进展中的纤溶酶原

基本信息

批准号：
10410524
负责人：
Kirk N Campbell
金额：
$ 53.69万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2020-07-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10410524
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

项目摘要

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.

项目总结