IgG glycosylation in lupus nephritis

狼疮性肾炎中的 IgG 糖基化

• 批准号: 10667421
• 负责人: Rhea Bhargava
• 金额: $ 12.25万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-18 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10667421
• 关键词: Advisory Committees; Affinity; Antigen-Antibody Complex; Area; Attenuated; Autoimmunity; Binding; Biological Markers; Biology; Biopsy; C-Type Lectins; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Calcium Signaling; Caring; Cells; Clinical; Clinical Research; Complication; Data; Deposition; Development; Disease remission; End stage renal failure; Excision; Exposure to; Fucose; Functional disorder; Galactose; Genetic; Glycoside Hydrolases; Goals; Hand; Immune; Immunoglobulin G; Immunoglobulins; Immunology; Individual; Injury; Kidney; Kidney Diseases; Knowledge; Laboratories; Lead; Learning; Lectin; Lupus Nephritis; Measurement; Measures; Mediating; Membrane; Mentorship; Modification; Morbidity - disease rate; Nephritis; Nephrology; Pathogenesis; Pathogenicity; Pathology; Patient Recruitments; Patients; Pattern; Pharmaceutical Preparations; Phase; Physicians; Polysaccharides; Population; Positioning Attribute; Preparation; Prevention; Process; Prospective Studies; Protein Kinase; Protein-Serine-Threonine Kinases; Renal function; Research; Research Project Summaries; Research Proposals; Risk; Role; SYK gene; Scheme; Scientist; Serology; Serum; Signal Transduction; System; Systemic Lupus Erythematosus; Techniques; Testing; Training; Translating; Up-Regulation; Urine; Work; aggressive therapy; blood filter; career; clinical remission; cohort; design; diagnostic tool; diagnostic value; experimental group; experimental study; glycosylated IgG; glycosylation; healthy volunteer; indexing; innovation; insight; kidney cell; liquid biopsy; lupus prone mice; mortality; pharmacologic; podocyte; prevent; prospective; recruit; sugar; systemic autoimmunity; tenure track; therapeutic target; translational research program; treatment response

PROJECT SUMMARY Research: Lupus nephritis (LN) is a serious complication occurring in more than 50% of patients with systemic lupus erythematosus (SLE) and dramatically worsens the mortality in this population. Despite the significant morbidity associated with LN, we lack biomarkers, specific medications, and a clear understanding of its pathogenesis. The ability to accurately identify SLE patients likely to develop LN could shift the current management paradigm from treatment to prevention and facilitate consideration of aggressive therapy to attenuate autoimmunity prior to kidney involvement. My preliminary data show that IgG from patients with LN is glycosylated differently from SLE patients without nephritis and when it enters podocytes it binds a lectin to initiate signaling processes which involves the upregulation of calcium/calmodulin kinase IV (CaMK4) leading to injury. Inhibiting CaMK4 in podocytes only, prevents immune complex deposition and nephritis in lupus prone mice. The objective of this research proposal is to test the hypothesis that aberrantly glycosylated IgG injures podocytes by upregulating CaMK4 in patients with LN through binding to the lectin CLEC7A in three sets of complementary experiments. In the first the glycosylation pattern of IgG will be characterized in patients with LN and control subjects including SLE patients without LN. In the second the signaling cascade that is triggered by IgG in podocytes will be defined. In the third, a pilot prospective study will be performed to determine whether measurement of CaMK4 levels in urine podocytes and in cultured podocytes exposed to serum IgG can reliably identify patients with LN. Successful completion of the proposed work will reveal new treatment and diagnostic tools to identify individuals with SLE destined to develop LN and follow response to treatment. Candidate Career Goals: My career goal is to become a successful academic physician-scientist leading a translational research program on the pathophysiology of immune complex-mediated kidney disease with a focus on lupus nephritis. To achieve this, I will work with experts in glycomics, immunology, pathology, SLE, nephrology and scientific innovation. The studies outlined in this application will be critical to obtain the training, knowledge, and expertise needed to successfully establish an independent translational research program integrating glycomics and immunology with kidney pathology and hold a tenure-track physician-scientist position in academic nephrology. The K99 phase will be performed under the mentorship of Dr. George Tsokos who is a known leader in the field of SLE, with guidance from an interdisciplinary Scientific Advisory Committee composed of experts in each of these areas specifically geared towards training in functional glycomics and advanced immunology. With this training in hand, the proposed R00 phase research will then establish lectin- glycan recognition systems and their signaling in lupus nephritis.

项目概要 研究：狼疮性肾炎 (LN) 是一种严重并发症，发生于超过 50% 的全身性肾病患者 红斑狼疮 (SLE) 并急剧恶化该人群的死亡率。尽管意义重大 对于与 LN 相关的发病率，我们缺乏生物标志物、特定药物以及对其的清晰了解 发病。准确识别可能发展为 LN 的 SLE 患者的能力可能会改变当前的情况 从治疗到预防的管理范式，并促进考虑积极治疗 在肾脏受累之前减弱自身免疫。我的初步数据显示，LN 患者的 IgG 是 糖基化与无肾炎的 SLE 患者不同，当它进入足细胞时，它会与凝集素结合 启动涉及钙/钙调蛋白激酶 IV (CaMK4) 上调的信号传导过程 以致受伤。仅抑制足细胞中的 CaMK4，可预防狼疮中的免疫复合物沉积和肾炎 易卧的小鼠。本研究计划的目的是检验 IgG 异常糖基化的假设 在三种情况下，通过与凝集素 CLEC7A 结合，上调 LN 患者的 CaMK4，从而损伤足细胞 一组互补的实验。首先，IgG 的糖基化模式将被表征为 患有 LN 的患者和对照受试者（包括无 LN 的 SLE 患者）。在第二个信号级联中 由足细胞中的 IgG 触发的信号将被定义。第三，将进行试点前瞻性研究 确定测量尿液足细胞和培养的足细胞中的 CaMK4 水平是否暴露于 血清 IgG 可以可靠地识别 LN 患者。成功完成拟议工作将揭示新的 治疗和诊断工具，用于识别患有 SLE 且注定会发生 LN 的个体，并跟踪对治疗的反应 治疗。 候选人职业目标：我的职业目标是成为一名成功的学术医师科学家，领导一个 免疫复合物介导的肾病病理生理学转化研究计划 重点关注狼疮性肾炎。为了实现这一目标，我将与糖组学、免疫学、病理学、SLE、 肾脏病学和科学创新。本申请中概述的研究对于获得培训至关重要， 成功建立独立转化研究计划所需的知识和专业知识 将糖组学和免疫学与肾脏病理学相结合，并拥有终身职位的医师科学家 在肾脏病学学术界的地位。 K99阶段将在George Tsokos博士的指导下进行 他是 SLE 领域的知名领导者，并得到跨学科科学咨询委员会的指导 由这些领域的专家组成，专门针对功能糖组学培训和 先进的免疫学。通过这次培训，拟议的 R00 阶段研究将建立凝集素- 狼疮性肾炎中的聚糖识别系统及其信号传导。