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

ANCA 肾小球肾炎的遗传变异和疾病状态的分子特征。

• 批准号: 9117493
• 负责人: DOMINIC J CIAVATTA
• 金额: $ 34.88万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9117493
• 关键词: Address; Affect; African American; Alleles; American; Amino Acid Sequence; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; Biological Markers; Cell Line; Cells; Clinical; Clinical Research; Collaborations; Computer Analysis; DNA Methylation; Data; Disease; Disease remission; Disease susceptibility; Epigenetic Process; Event; FDA approved; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Polymorphism; Genomics; Genotype; Glomerulonephritis; Goals; HLA Antigens; Health; Histone Code; Investigation; Lead; Legal patent; Leukocytes; Light; Maps; Measurement; Mining; Molecular; Molecular Profiling; Monitor; Myelogenous; Myeloid Cells; Output; PRTN3 gene; Pathogenesis; Patients; Peptides; Pharmaceutical Preparations; Predisposition; Principal Investigator; Program Research Project Grants; Quantitative Trait Loci; Relapse; Research; Research Personnel; Sampling; Severities; Severity of illness; Signal Transduction; Staging; Surveys; System; T cell response; T-Lymphocyte; Testing; Therapeutic Agents; Transcript; Translations; Variant; Vasculitis; Work; Yang; abstracting; autoreactive T cell; base; biomarker development; biomarker identification; cell type; cohort; disease phenotype; epigenetic regulation; epigenetic variation; epigenome; genetic association; genetic variant; genome wide association study; genome-wide; granulocyte; histone modification; human data; improved; interest; man; monocyte; neutrophil; novel therapeutic intervention; novel therapeutics; profiles in patients; risk variant; targeted treatment; tool; transcriptome; transcriptome sequencing; transcriptomics

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?

项目1摘要 项目1的目标是定义负责原因，严重性和 ANCA肾小球肾炎（GN）的治疗。 AIM 1将解决遗传基础 使用全基因组相关研究（GWA）的结果对ANCA GN的敏感性 美国ANCA GN患者与血管炎临床合作进行 研究联盟，包括来自UNC患者队列的550多个样本。协会 在此GWAS中发现的良好映射可以鉴定人白细胞中的遗传变异 抗原（HLA）基因。特定HLA变体的计算分析可以预测潜力 煽动自身抗原肽。这些肽将用于鉴定自动反应性T细胞和 表征这些T细胞的响应。这个目标的结果将告知导致的 某些人的疾病，可能通过耐受患者煽动来提供潜在的疗法 自动抗原。 AIM 2和3我们将剖析区分活性疾病和的分子事件 缓解。 AIM 2基于牵涉自身抗原表达的研究与与自身抗原的表达相关 疾病活动和活跃或恢复疾病的患者之间的表达差异 受表观遗传变化的调节。组蛋白修饰的分布和水平以及 DNA甲基化将显示出一种表观遗传学特征，将活动疾病与 缓解。这些结果将为使用针对表观遗传学的疗法提供理由 规定。 AIM 3将调查总白细胞和4个不同细胞的转录格局 在 ANCA GN。基因表达结果将用于建立转录签名 区分活性疾病与缓解。该特征中的一个基因子集面板 可用于监测疾病状况，最终可以指导临床医生选择 治疗。表达数据将用GWAS到MAP表达的基因型询问 与疾病活性相关的定量性状基因座。最后，AIM 3将直接解决这个问题 通过比较ANCA GN患者的转录特征与 连接图，这是单元线之间转录变化的汇编 用FDA批准的药物治疗。此比较将确定苦恼或 对抗ANCA GN中的转录签名，重要的是， 重新利用药物来治疗ANCA GN。项目1解决了患者的主要问题 ANCA GN：是什么原因引起了这种疾病？是什么使它变得更加严重？怎么会 治疗？