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: 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
• 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

 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提高申请人的学习和研究技能，以过渡为独立研究者。该奖项的职业发展方面得到了他的指导团队、相关课程、期刊俱乐部、研讨会、大学中心以及致力于加强临床医生和研究人员之间合作的核心的促进。该提案的研究部分重点关注导致进行性肾脏损伤的自身免疫性疾病 IgA 肾病 (IgAN) 以及自身抗原的产生机制。识别自身抗原产生所涉及的机制将有助于开发针对疾病的特异性疗法，而这在当前的治疗方式中是不存在的。这给 IgAN 患者带来了巨大的金钱负担和生活质量负担。 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。这将通过与在分子生物学研究，特别是 IgAN 和肾脏相关疾病方面拥有丰富经验的导师合作来完成。该大学设有特殊的核心项目，旨在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、研究培训项目和实验室管理课程。 IgAN 是一种自身免疫性疾病，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 细胞产生具有异常糖基化的 IgA1（称为 Gd-IgA1），导致身体将 IgA1 识别为外来抗原。 IgAN 患者的自身抗原 Gd-IgA1 升高，并形成免疫复合物形成的基础，免疫复合物沉积在肾脏中，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 产量升高的机制。在 IgAN 患者 B 细胞中鉴定出受细胞因子差异调节和过度激活信号转导子和转录激活子 3 (STAT3) 的特定糖基化酶，为我们提供了一个强有力的起点。我们建议研究 IgAN 患者信号改变的机制，从而为未来减少自身抗原产生的药物开发提供基础。