IgG glycosylation in lupus nephritis

项目总结 研究：狼疮性肾炎(LN)是一种严重的并发症，发生在超过50%的系统性红斑狼疮患者中 红斑狼疮(SLE)和极大地恶化了这一人群的死亡率。尽管重要的是 与LN相关的发病率，我们缺乏生物标记物、特定的药物以及对其 发病机制。准确识别可能发展为LN的SLE患者的能力可能会改变目前的 从治疗到预防的管理范式和促进积极治疗的考虑 在肾脏受累之前减弱自身免疫力。我的初步数据显示LN患者的免疫球蛋白是 糖基化与非肾炎的SLE患者不同，当它进入足细胞时，它与凝集素结合 启动涉及钙/钙调蛋白激酶IV(CaMK4)引导上调的信号转导过程 致伤。仅抑制足细胞中的CaMK4可预防狼疮免疫复合物沉积和肾炎 易受攻击的老鼠。这项研究提案的目的是检验异常糖基化的免疫球蛋白G的假说 3例LN患者通过与凝集素CLEC7A结合上调CaMK4损伤足细胞 一组互补的实验。首先，免疫球蛋白的糖基化模式将被描述为 LN患者和对照组包括无LN的SLE患者。在第二个阶段，信号级联 这是由足细胞中的免疫球蛋白触发的，将被定义。在第三项研究中，将进行一项试验性前瞻性研究，以 确定尿足细胞和培养足细胞中CaMK4水平的测量是否暴露于 血清免疫球蛋白可可靠地诊断LN患者。拟议工作的成功完成将揭示新的 治疗和诊断工具，以识别注定要发展为LN的SLE患者，并跟踪对 治疗。 求职者的职业目标：我的职业目标是成为一名成功的学术内科医生-科学家，领导一个 免疫复合体介导的肾病的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、系统性红斑狼疮、 肾病学和科学创新。本申请中概述的研究将是获得培训的关键， 成功建立独立的翻译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，并拥有终身医师-科学家 在学术肾脏病学方面的地位。K99阶段将在George Tsokos博士的指导下进行 世卫组织在跨学科科学咨询委员会的指导下，是SLE领域的已知领导者 由这些领域的专家组成，专门针对功能糖组学培训和 高级免疫学。有了这项培训，拟议的R00阶段研究将建立凝集素- 狼疮性肾炎中的糖链识别系统及其信号转导。

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.