Biomarking IBD patient-specific disease features using the epithelial antigenic peptidome

使用上皮抗原肽组对 IBD 患者特异性疾病特征进行生物标记

• 批准号: 10261547
• 负责人: JONATHAN BRAUN
• 金额: $ 20.88万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-11 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10261547
• 关键词: Address; Age; Algorithms; Antibodies; Archives; Autoantibodies; Autoimmune Process; Autoimmunity; Base Sequence; Binding Proteins; Bioinformatics; Biological Markers; Cells; Chronic; Clinical; Colectomy; Complementary DNA; Crohn' s disease; Diabetes Mellitus; Disease; Disease Progression; Effectiveness; Environmental Exposure; Epithelial; Epitopes; Foundations; Genetic; Genetic Diseases; Genomics; Goals; Human; Immune; Immunologics; Incidence; Individual; Inflammatory; Inflammatory Bowel Diseases; Injury; Insulin-Dependent Diabetes Mellitus; Libraries; Link; Mediating; Metadata; Modernization; Mucous Membrane; National Institute of Diabetes and Digestive and Kidney Diseases; Oligonucleotides; Outcome; Pathogenesis; Pathogenicity; Patients; Peptides; Phenotype; Population; Pouchitis; Prognosis; Prognostic Marker; Proteins; Research Priority; Risk; Role; Sampling; Serum; Specificity; Subgroup; Technology; Testing; Time; Ulcerative Colitis; base; clinical application; clinical biomarkers; cohort; disease phenotype; disorder control; genomic locus; host microbiome; innovation; microbiome; patient subsets; pre-clinical; study population; technological innovation; therapeutic target; unsupervised learning

Project Summary/Abstract In immune-mediated diseases such as type1 diabetes, target-cell autoantibodies have emerged as important clinical biomarkers of pre-clinical disease progression and mechanistic disease subsets. However, with the focus on genetics, inflammatory effectors, and microbiome, there has not been a modern search for such antibody biomarkers and the potential contribution of anti-epithelial autoimmunity in IBD. This project tests the hypothesis that ulcerative colitis phenotypes are distinguished by autoantibodies to mucosal epithelial proteins, addressed in two aims. In the first aim, we apply the innovative peptide expression display (PED) technology to display and analyze the antigenic epithelial peptidome. This includes bioinformatically determining a comprehensive tabulation of human proteins with high likelihood for antigenicity and ileal-colonic epithelial expression; and, representing these proteins as tiled peptide epitopes with linked cognate oligonucleotides suitable for NGS-based identification and quantitation. In the second aim, we will assess archival sera of 654 well-characterized colonic IBD patients and non-IBD controls to quantitate individual profiles of epithelial protein binding in relation to two outcomes of ulcerative colitis (UC). The significance of the project has been endorsed by the IBD Genetics Consortium (IBDGC), which made the UC colectomy cohort a research priority, and will collaborate with this R21 via archival serum samples and associated genetics and clinical metadata from the consortium UC patients and controls. Our primary study will compare 300 UC subjects, equally divided into severe and mild phenotypes of outcome based on time to colectomy. Our secondary study will compare 154 UC post-colectomy pouch patients, divided into severe and absent pouchitis phenotypes. We will also study two age-matched reference populations. Bioinformatic analyses will test for shared peptide specificities associated with disease state (UC vs. non-IBD controls) and each of the two extreme phenotypes (severe vs. mild UC; chronic pouchitis vs. late non-pouchitis). We also will perform exploratory tests for the role of IBD predictive risk scores and select genetic loci on autoantibody specificities. If successful, this project will establish feasibility for the hypothesis, and foundational targets to pursue mechanistic and clinical biomarker studies that may validate and refine its implications for IBD pathogenesis and clinical applications.

项目总结/摘要 在免疫介导的疾病如1型糖尿病中，靶细胞自身抗体具有 作为临床前疾病进展的重要临床生物标志物， 疾病亚群然而，随着对遗传学、炎症效应器和微生物组的关注， 还没有对这种抗体生物标志物的现代研究， 抗上皮自身免疫性炎症这个项目测试了溃疡性结肠炎 表型通过针对粘膜上皮蛋白的自身抗体来区分，在两个 目标。 在第一个目标中，我们应用创新的肽表达展示（PED）技术， 显示和分析抗原上皮肽组。这包括生物信息学 确定具有高抗原性可能性的人蛋白质的综合列表 和回肠-结肠上皮表达;并且，将这些蛋白质表示为平铺肽表位 连接的同源寡核苷酸适合于基于NGS的鉴定和定量。 在第二个目标中，我们将评估654例特征明确的结肠IBD患者的存档血清， 患者和非IBD对照，以定量上皮蛋白结合的个体概况， 与溃疡性结肠炎（UC）的两种结局相关。该项目的重要性一直是 IBD遗传学联盟（IBDGC）认可，这使得UC结肠切除术队列成为一个 研究优先，并将通过档案血清样本和相关的R21合作， 遗传学和临床元数据从联盟UC患者和对照。我们的主要研究 将比较300例UC受试者，根据结局分为重度和轻度表型 按时进行结肠切除术。我们的第二项研究将比较154名UC结肠切除术后袋患者， 分为严重和不存在的结肠袋炎表型。我们还将研究两个年龄匹配的 参考人群。生物信息学分析将测试与基因突变相关的共享肽特异性。 疾病状态（UC vs.非IBD对照）和两种极端表型（重度 vs.轻度UC;慢性结肠袋炎vs.晚期非结肠袋炎）。我们还将进行探索性测试， IBD预测风险评分和选择遗传位点对自身抗体特异性的作用。 如果成功的话，这个项目将为假设建立可行性， 目标是进行机制和临床生物标志物研究，以验证和完善其 IBD发病机制和临床应用的意义。