Cytotoxic T cells in Ulcerative Colitis

溃疡性结肠炎中的细胞毒性 T 细胞

• 批准号: 9922904
• 负责人: Arnold Han
• 金额: $ 8.1万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922904
• 关键词: Adaptive Immune System; Affect; American; Antigen Receptors; Antigen Targeting; Antigens; Automobile Driving; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cells; Child; Chronic; Clone Cells; Colon; Complex; Crohn' s disease; Cytotoxic T-Lymphocytes; Data; Disease; Functional disorder; Gene Expression Profile; Glean; Goals; Helper-Inducer T-Lymphocyte; Human; Immunologic Memory; Impairment; Incidence; Inflammatory Bowel Diseases; Innate Immune System; Intestines; Masks; Mediating; Medical; Methods; Morbidity - disease rate; Mucous Membrane; Natural Immunity; Operative Surgical Procedures; Organoids; Patients; Peptides; Persons; Pharmacology; Phenotype; Population; Research; Signal Transduction; Specificity; Stimulus; T cell response; T-Cell Receptor; T-Lymphocyte; Therapeutic; Tissues; Treatment Cost; Ulcerative Colitis; adaptive immune response; cell type; colon cancer risk; cost; cytotoxic CD8 T cells; design; high dimensionality; improved; inflammatory disease of the intestine; innovation; insight; interest; intestinal barrier; member; microorganism; novel; novel therapeutics; response; screening; single cell analysis; targeted treatment; therapeutic target; tool; transcription factor; transcriptome

Project Summary Inflammatory bowel diseases (IBD), comprised of Crohn’s disease (CD) and ulcerative colitis (UC), afflict approximately one million Americans and millions more worldwide. Alarmingly, the overall incidence of IBD is increasing, and increasing in children and persons in whom IBD had previously been uncommon. In addition to significant impairment from intestinal inflammation, affected patients suffer from extra-intestinal manifestations of disease, morbidities from medical and surgical treatment, and increased risk of colon cancer. Treatments are costly and ineffective in many patients. The mechanisms of IBD are complex and therefore not well understood. The importance of T cells in mediating aberrant adaptive immune responses in IBD is well established, however, the mechanisms through which T cells mediate disease remain unclear. While it is likely that CD4+ T cells guide and regulate CD8+ T cell responses, the end effectors that drive tissue damage are likely cytotoxic CD8+ T cells. Our proposal specifically aims to identify and study effector CD8+ T cells in UC- the cells we propose are responsible for tissue damage. Our team recently developed novel tools that enable us to glean unprecedented amounts of information from single T cells, accurately identify their TCR sequence, and query their antigen specificity. Our central hypothesis is that Bcl6-expressing CD8+ T cells drive tissue damage in UC. Further, we hypothesize that they are responding to locally derived signals. If so, we reason that these locally derived signals can be pharmacologically targeted. We will investigate these hypotheses through the following specific aims: 1) Investigate mechanisms of intestinal damage in ulcerative colitis through the single-cell study and functional characterization of bcl6-expressing CD8+ T cells. 2) Investigate antigen specificity of bcl6-expressing CD8+ T cells through intestinal organoids and random peptide screening. Successful completion of these aims could have important implications in therapies. The proposed research is innovative because it applies innovative methods to study T cell function within UC through single-cell analysis of TCR-matched cells from inflamed vs. non-inflamed colon within the same patients. Our own expertise and the expertise of our collaborators make us uniquely qualified to perform these studies.

项目摘要 炎症性肠病(IBD)，包括克罗恩病(CD)和溃疡性结肠炎(UC)， 大约有100万美国人和全球数百万人。令人担忧的是，IBD的总发病率是 在以前IBD不常见的儿童和人群中，IBD的发病率不断上升。除了……之外 肠道炎症造成的明显损害，受影响的患者出现肠外症状 疾病的发病率、内科和外科治疗的发病率以及结肠癌风险的增加。治疗 对许多患者来说是昂贵和无效的。IBD的发病机制很复杂，因此并不是很好。 明白了。T细胞在介导IBD异常适应性免疫反应中的重要性 然而，T细胞介导疾病的机制仍然不清楚。虽然很有可能 CD4+T细胞引导和调节CD8+T细胞反应，驱动组织损伤的最终效应器是 可能是细胞毒CD8+T细胞。我们的建议旨在鉴定和研究UC中的CD8+T细胞。 我们提出的细胞是造成组织损伤的原因。我们的团队最近开发了新的工具，使 美国将从单个T细胞收集前所未有的大量信息，准确识别它们的TCR序列， 并对其抗原特异性提出质疑。我们的中心假设是，表达Bcl6的CD8+T细胞驱动组织 UC损坏。此外，我们假设它们是对本地派生的信号做出反应。如果是这样的话，我们推断 这些局部派生的信号在药理上是有针对性的。我们将调查这些假设 通过以下具体目的：1)通过以下途径探讨溃疡性结肠炎的肠道损伤机制 表达Bcl6的CD8+T细胞的单细胞研究及功能鉴定。2)调查抗原 肠道器官和随机多肽筛选表达Bcl6的CD8+T细胞的特异性 这些目标的成功实现可能会对治疗产生重要影响。拟议的研究是 创新是因为它应用了创新的方法，通过单细胞分析来研究UC内的T细胞功能 同一患者的发炎结肠和非发炎结肠的TCR配对细胞。我们自己的专业知识和 我们的合作者的专业知识使我们独一无二地有资格进行这些研究。