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Abnormal STAT3 signaling and aberrant O-glycosylation of IgA1 in IgA nephropathy

IgA 肾病中 STAT3 信号异常和 IgA1 异常 O-糖基化

基本信息

批准号：
8949844
负责人：
Colin Robert Reily
金额：
$ 15.42万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8949844
关键词：
Affect Antigen-Antibody Complex Antigens Autoantibodies Autoantigens Autoimmune Diseases Automobile Driving Award B-Lymphocytes Binding Biological Markers Blood specimen Cell Line Cells Clinical Collaborations Data Deposition Dialysis procedure Disease Disease Progression End stage renal failure Enzymes Extracellular Matrix Flare Future Galactose Goals Grant Hematuria IgA1 Immune Immune system Immunoglobulin A Individual Infection Injury Interleukin-6 Janus kinase Journals K-Series Research Career Programs Kidney Kidney Diseases Kidney Glomerulus Kidney Transplantation Learning Mentors Modality Molecular Molecular Biology Monitor National Institute of Diabetes and Digestive and Kidney Diseases Pathology Pathway interactions Patients Peripheral Blood Lymphocyte Phenotype Phosphoric Monoester Hydrolases Polysaccharides Postdoctoral Fellow Production Quality of life Regulation Regulatory Pathway Renal function Research Research Personnel Research Training Serum Signal Transduction Site Small Interfering RNA Stat3 protein Structure of glomerular mesangium Testing Therapeutic Time Training Training Programs Translating Transplantation Universities Writing base career development cost cytokine drug development experience glycosylation glycosyltransferase inhibitor/antagonist insight knock-down new therapeutic target novel therapeutic intervention programs public health relevance receptor skills small molecule therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The purpose of this proposal for the K01 Career Development Award from the NIDDK is to enhance the learning and research skills of the applicant in order to transition into an independent investigator. The career development aspect of this award is facilitated by his mentoring team, relevant courses, journal clubs, seminars, university centers, and cores dedicated to enhancing collaboration between clinicians and researchers. The research portion of this proposal is focused on the autoimmune disease IgA nephropathy (IgAN), which causes progressive kidney damage, and the mechanisms of autoantigen production. Identification of mechanisms involved in autoantigen production will allow for disease-specific therapies to be developed, which is absent in current therapeutic modalities. This has a huge cost burden on IgAN patients, both in terms of money and quality of life. The long-term goal of the applicant is to become an independent investigator, and as a current postdoc this will require more training and experience. This will be accomplished through collaboration with mentors who have extensive experience in molecular biology research, and specifically IgAN and kidney related diseases. The university has exceptional core programs set up to help young investigators with finding and writing grants, obtaining proper collaborative expertise, research training programs, and lab management courses. IgAN is an autoimmune disease, which leads to decreased kidney function, with 40-50% of patients requiring dialysis and/or transplantation. In this autoimmune disease, B cells from the immune system produce IgA1 that has an aberrant glycosylation (termed Gd-IgA1) that causes the body to recognize IgA1 as a foreign antigen. The autoantigen, Gd-IgA1, is elevated in IgAN patients and forms the basis for immune-complex formation, which deposits in the kidney, leading to progressive kidney damage. The aims of this proposal are to identify mechanisms responsible for elevated Gd-IgA1 production in patient B cells. Identification of specific glycosylation enzymes that are differentially regulated and over activation signal transducer and activator of transcription 3 (STAT3) by cytokines in IgAN patient B cells has provided us with a strong starting point. We propose to investigate mechanisms responsible for altered signaling in IgAN patients, thereby providing bases for future drug development to reduce autoantigen production.