IgG glycosylation in lupus nephritis

项目摘要 狼疮性肾炎（LN）是一种严重的并发症，发生在超过50%的全身性肾炎患者中。 红斑狼疮（SLE），并显着降低了这一人群的死亡率。增速出现明显 与LN相关的发病率，我们缺乏生物标志物，具体的药物，并清楚地了解其 发病机制准确识别可能发展为LN的SLE患者的能力可以改变目前的 从治疗到预防的管理模式，并促进考虑积极的治疗， 在肾脏受累之前减弱自身免疫性。我的初步数据显示LN患者的IgG 糖基化不同于没有肾炎的SLE患者，当它进入足细胞时，它结合凝集素， 启动涉及钙/钙调蛋白激酶IV（CaMK 4）上调的信号传导过程， 受伤。仅抑制足细胞中的CaMK 4可预防狼疮中的免疫复合物沉积和肾炎 俯卧的老鼠本研究的目的是检验异常糖基化IgG 在LN患者中，通过与三种细胞中的凝集素CLEC7A结合，通过上调CaMK 4损伤足细胞。 几组互补的实验。在第一个中，IgG的糖基化模式将被表征为： LN患者和对照组（包括无LN的SLE患者）。第二种是信号级联 将定义由足细胞中的IgG触发的。第三，将进行一项前瞻性试点研究， 确定尿足细胞和暴露于以下物质的培养足细胞中的CaMK 4水平的测量是否 血清IgG能可靠地鉴别LN患者。成功完成拟议的工作将揭示新的 治疗和诊断工具，以识别注定发展LN的SLE个体，并跟踪对 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物理学家，科学家，领导一个 免疫复合物介导的肾病病理生理学的转化研究计划， 狼疮性肾炎怎么办为了实现这一目标，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，并拥有终身医学科学家 在学术肾脏病学中的地位。K99阶段将在乔治Tsokos博士的指导下进行 他是SLE领域的知名领导者，在跨学科科学咨询委员会的指导下， 由这些领域的专家组成，专门针对功能性糖组学的培训， 先进的免疫学有了这项培训，拟议的R00阶段研究将建立凝集素- 狼疮性肾炎中的聚糖识别系统及其信号传导。

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.