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

• 批准号: 9750059
• 负责人: Colin Robert Reily
• 金额: $ 15.27万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750059
• 关键词: Affect; Antigen-Antibody Complex; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; Automobile Driving; Award; B-Lymphocytes; 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; IGA Glomerulonephritis; IgA1; Immune; Immune system; Immunoglobulin A; Individual; Infection; Injury; Interleukin 6 Receptor; Interleukin-6; Janus kinase; Journals; K-Series Research Career Programs; Kidney; Kidney Glomerulus; Kidney Transplantation; Learning; Mentors; Modality; Molecular; Molecular Biology; Monitor; Mucous Membrane; National Institute of Diabetes and Digestive and Kidney Diseases; Pathogenicity; Pathologic; 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; insight; knock-down; new therapeutic target; novel therapeutic intervention; potential biomarker; programs; public health relevance; renal damage; skills; small molecule inhibitor; therapeutic target

 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.

 描述（由申请人提供）：NIDDK K01 职业发展奖提案的目的是加强申请人的学习和研究，以促进该奖项技能的职业发展。由他的指导团队、相关课程、期刊俱乐部、研讨会、大学中心和致力于加强新人与研究人员之间合作的核心组成，该提案的研究部分重点关注自身免疫性疾病 IgA 肾病。 （IgAN）会导致进行性肾脏损伤，而自身抗原产生的机制的识别将有助于开发特定疾病的疗法，而这在当前的治疗方式中是不存在的。 IgAN 患者，无论是在金钱还是生活质量方面，申请人的长期目标是成为一名独立研究者，作为目前的博士后，这将需要更多的培训和经验，这将通过与导师的合作来完成。拥有丰富的经验该大学设立了特殊的核心项目，以帮助年轻研究人员寻找和撰写资助、获得适当的合作专业知识、研究培训计划和实验室管理课程。这会导致肾功能下降，40-50% 的患者需要透析和/或移植。在这种自身免疫性疾病中，免疫系统的 B 细胞会产生糖基化异常的 IgA1（称为糖基化）。 Gd-IgA1）导致身体将 IgA1 识别为外来抗原 IgAN 患者中存在自身抗原，Gd-IgA1 是免疫复合物形成的基础，该抗原在肾脏中沉积升高，导致进行性肾脏损伤。该提案的目的是确定患者 B 细胞中 Gd-IgA1 产生升高的机制，识别差异调节和过度激活信号转导器的特定糖基化酶。因此，IgAN 患者 B 细胞中细胞因子的转录激活子 3 (STAT3) 为我们提供了一个强有力的起点，我们建议研究 IgAN 患者中信号传导改变的机制，为未来减少自身抗原产生的药物开发提供基础。