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 项目1的目标是定义负责原因、严重程度和 ANCA肾小球肾炎（GN）的治疗。目标1将解决以下问题的遗传基础 使用来自北卡罗来纳州的全基因组相关研究（GWAS）的结果， 美国ANCA GN患者与血管炎临床合作进行 研究联盟，并包括超过550个样本，从一个糖尿病患者队列。协会 在这个GWAS中发现的基因将被精细映射，以识别人类白细胞内的遗传变异。 抗原（HLA）基因。特定HLA变体的计算分析可以预测潜在的 刺激自身抗原肽。这些肽将用于鉴定自身反应性T细胞， 描述这些T细胞的反应。这一目标的结果将告知是什么原因造成的 疾病，并可能提供一个潜在的治疗，使患者耐受的煽动， 自身抗原目的2和3我们将剖析区分活动性疾病和 缓解。目的2是基于涉及自身抗原表达的研究， 疾病活动性和活动性或缓解性疾病患者之间的表达差异 是由表观遗传变化调节的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， 缓解。这些结果将为使用针对表观遗传的治疗提供理论基础。 调控目的3将调查总白细胞和4种不同细胞的转录景观 类型（中性粒细胞，单核细胞，T细胞和髓源性抑制样细胞）在 ANCA GN.基因表达结果将用于建立转录特征， 区分活动期和缓解期。一组在这个特征中的基因子集 可用于监测疾病状态，最终可指导临床医生选择 疗法将使用来自GWAS的基因型查询表达数据，以绘制表达图谱 与疾病活动相关的数量性状位点。最后，目标3将直接解决这个问题 通过比较ANCA GN患者与非ANCA GN患者的转录谱， 连接图，这是细胞系之间转录变化的汇编， 使用FDA批准的药物治疗。这种比较将确定药物， 拮抗ANCA GN中的转录签名，重要的是，这是 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：是什么导致了这种疾病？是什么让它更严重或更不严重？怎么会 治疗？