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

 描述（由申请人提供）：NIDDK的K 01职业发展奖提案的目的是提高申请人的学习和研究技能，以便过渡到独立调查员。该奖项的职业发展方面是由他的指导团队，相关课程，期刊俱乐部，研讨会，大学中心和致力于加强临床医生和研究人员之间的合作核心促进。该提案的研究部分集中在自身免疫性疾病伊加肾病（IgAN），导致进行性肾损伤，以及自身抗原产生的机制。鉴定自身抗原产生的机制将允许开发疾病特异性疗法，这在当前的治疗方式中是缺乏的。这给IgAN患者带来了巨大的成本负担，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的研究人员，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具有丰富经验的导师合作来实现。该大学有特殊的核心计划，以帮助年轻的研究人员寻找和撰写赠款，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。 IgAN是一种自身免疫性疾病，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，来自免疫系统的B细胞产生具有异常糖基化的IgA 1（称为Gd-IgA 1），其导致身体将IgA 1识别为外来抗原。自身抗原Gd-IgA 1在IgAN患者中升高，并形成免疫复合物形成的基础，免疫复合物沉积在肾脏中，导致进行性肾损伤。该建议的目的是确定负责患者B细胞中Gd-IgA 1产生升高的机制。在IgAN患者B细胞中通过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（STAT 3）的特异性糖基化酶的鉴定为我们提供了强有力的起点。我们建议调查机制负责改变信号在IgAN患者，从而为未来的药物开发，以减少自身抗原的生产提供基础。

 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.