Genetic variants in ANCA glomerulonephritis and molecular signatures of disease states.

项目1摘要 项目1的目标是定义导致原因、严重性和 ANCA肾炎(GN)的治疗。目标1将阐述基因基础 应用北方全基因组相关研究结果研究ANCA-GN的易感性 美国ANCA GN患者与脉管炎临床联合手术 研究联盟，包括来自北卡罗来纳大学患者队列的550多个样本。联谊会 在此GWAS中发现的将被精细定位以识别人类白细胞内的遗传变异 抗原(人类白细胞抗原)基因。对特定的人类白细胞抗原变异的计算分析可以预测潜在的 激发自身抗原肽。这些多肽将用于识别自身反应性T细胞和 描述这些T细胞的反应。这一目标的结果将告知是什么导致了 在一些人中的疾病，并可能提供一种潜在的治疗方法，通过容忍患者对煽动 自身抗原。目标2和3我们将剖析区分活动性疾病和 减刑。AIM 2的基础是有研究表明，自身抗原的表达与 活动期和缓解期疾病活动性及其表达的差异 受表观遗传变化的调控。组蛋白修饰和组蛋白修饰的分布和水平 DNA甲基化将揭示一种表观遗传特征，将活动性疾病与 减刑。这些结果将为使用针对表观遗传学的疗法提供理论基础。 监管。目的3将研究总白细胞和4种不同细胞的转录图谱 类型(中性粒细胞、单核细胞、T细胞和髓系来源的抑制样细胞)在 Anca GN.基因表达结果将被用来建立转录签名， 区分活动性疾病和缓解性疾病。此签名内的基因子集的面板 可用于监控疾病状态，最终可指导临床医生选择 心理治疗。表达数据将与来自GWAS的基因类型一起查询以绘制表达图 与疾病活动性相关的数量性状基因座。最后，目标3将直接解决这个问题。 通过比较ANCA GN患者和ANCA GN患者的转录谱来指导治疗 连接图，这是对以下细胞系之间转录变化的汇编 使用FDA批准的药物进行治疗。这种比较将确定使人痛苦或痛苦的药物 拮抗ANCA GN中的转录签名，重要的是，这是 改变治疗ANCA GN的药物用途。项目1解决了患者的主要问题 Anca GN：是什么导致了这种疾病？是什么让它变得更严重或更不严重？怎么可能呢？ 治疗？

Project 1 Abstract The goals of Project 1 are to define molecular events responsible for cause, severity, and treatment of ANCA glomerulonephritis (GN). Aim 1 will address the genetic basis for susceptibility to ANCA GN using results from a genome-wide associated study (GWAS) of North American patients with ANCA GN performed in collaboration with the Vasculitis Clinical Research Consortium and included over 550 samples from a UNC patient cohort. Associations found in this GWAS will be fine mapped to identify genetic variants within human leukocyte antigen (HLA) genes. Computational analysis of specific HLA variants can predict potential inciting autoantigen peptides. These peptides will used to identify autoreactive T cells and characterize the response of these T cells. The results of this aim will inform what causes the disease in some people and may provide a potential therapy by tolerizing patients to the inciting autoantigen. Aim 2 and 3 we will dissect molecular events that distinguish active disease from remission. Aim 2 is based on studies implicating expression of the autoantigen correlates with disease activity and the expression differences between patients with active or remitting disease are regulated by epigenetic changes. The distribution and levels of histone modifications and DNA methylation will reveal an epigenetic signature that distinguishes active disease from remission. These results will provide a rationale for using therapies targeted against epigenetic regulation. Aim 3 will survey the transcriptional landscape of total leukocytes and 4 different cell types (neutrophils, monocytes, T cells, and myeloid derived suppressor-like cells) important in ANCA GN. Gene expression results will be used to establish a transcriptional signature that distinguishes active disease from remission. A panel of a subset of genes within this signature can be used to monitor disease status, which could ultimately guide clinicians in their choice of therapy. Expression data will be interrogated with genotypes from GWAS to map expression quantitative trait loci associated with disease activity. Finally, Aim 3 will directly tackle the issue of therapy by comparing the transcriptional profiles from patients with ANCA GN to the Connectivity Map, which is a compilation of transcriptional changes among cells lines following treatment with FDA approved drugs. This comparison will identify drugs that agonize or antagonize the transcriptional signature in ANCA GN, and importantly, is the rationale for repurposing drugs to treat ANCA GN. Project 1 addresses the primary questions of patients with ANCA GN: What caused the disease? What makes it more or less severe? How can it be treated?