T cell repertoire for hybrid insulin peptides

混合胰岛素肽的 T 细胞库

基本信息

批准号：
10170349
负责人：
KATHRYN M HASKINS
金额：
$ 49.27万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10170349
关键词：
Antigen Targeting Antigens Applications Grants Autoantigens Autoimmune Diabetes Autoimmune Process Autoimmunity Biological Assay Biological Markers C-Peptide CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell Line Cells Chromogranin A Clone Cells Disease Disease Progression Epitopes Frequencies Gene Expression Genomics Goals Human Hybrids Inbred NOD Mice Inflammatory Insulin Insulin-Dependent Diabetes Mellitus Interferon Type II Ligands Longitudinal Studies Monitor N-terminal Paper Pathogenesis Pathogenicity Patients Peptide Library Peptides Peripheral Blood Mononuclear Cell Phenotype Post-Translational Protein Processing Prevention strategy Proteins Proteomics Publishing Regulation Research Research Personnel Risk Role Science Source System T cell response T-Cell Immunologic Specificity T-Lymphocyte Testing Time Work antigen detection biomarker discovery combinatorial design detection platform diabetic patient diabetogenic disorder prevention enzyme linked immunospot assay human subject in vivo islet islet amyloid polypeptide neoantigens novel peripheral blood protein aminoacid sequence prototype screening single-cell RNA sequencing transcriptomics

项目摘要

Project Abstract Identification of the autoantigens that drive the pathogenic T cell response in type 1 diabetes (T1D) is a research goal of great importance because of the implications for biomarker discovery and disease prevention strategies. Our lab has focused on the role of CD4 T cells in both pathogenesis and regulation of disease with particular emphasis on their target antigens. Using a proteomic approach and the BDC panel of CD4 T cell clones as our antigen detection system, we recently discovered that the peptide ligands that activate several clones in our panel, including the prototype clone BDC-2.5, were formed through a novel post-translational modification involving formation of hybrid peptides between peptide cleavage products of -cell proteins such as ChgA or IAPP and sequences from insulin C-peptide. The discovery of hybrid insulin peptides (HIPs) as a new class of neoantigens raises questions as to the extent of HIP reactivity in T1D and whether T cells reactive to HIPs drive the autoimmune process. We hypothesize that HIP-reactive T cells can serve as biomarkers of disease and that the discovery of new HIP reactivities in NOD mice and patients with T1D will offer new possibilities to stage the disease before it occurs. To test this hypothesis, we propose to (1) investigate the T cell repertoire for hybrid insulin peptides (HIPs) in the NOD mouse; (2) discover C-peptide HIP reactivities using combinatorial peptide pools in T1D and at risk subjects and (3) monitor phenotype and TCR of HIP-reactive T cells over time in subjects at risk for T1D.

项目摘要识别驱动 1 型糖尿病 (T1D) 致病性 T 细胞反应的自身抗原是一项重要任务由于对生物标志物发现和疾病的影响，研究目标非常重要我们的实验室重点研究 CD4 T 细胞在发病机制和调节中的作用。使用蛋白质组学方法和 BDC 来研究疾病，特别强调其靶抗原。 CD4 T 细胞克隆组作为我们的抗原检测系统，我们最近发现肽配体激活我们面板中的几个克隆，包括原型克隆 BDC-2.5，是通过新颖的翻译后修饰涉及肽裂解之间杂合肽的形成  细胞蛋白的产物，例如 ChgA 或 IAPP 以及胰岛素 C 肽序列的发现。混合胰岛素肽（HIP）作为一类新的新抗原引发了关于 HIP 范围的问题 T1D 的反应性以及 T 细胞对 HIP 的反应是否驱动自身免疫过程。 HIP 反应性 T 细胞可以作为疾病的生物标志物，新的 HIP 反应性的发现 NOD 小鼠和 T1D 患者将为在疾病发生前进行分期测试提供新的可能性。根据这一假设，我们建议 (1) 研究混合胰岛素肽 (HIP) 的 T 细胞库 NOD 小鼠；(2) 使用组合肽池发现 T1D 和处于危险中的 C 肽 HIP 反应性 (3) 监测有 T1D 风险的受试者中 HIP 反应性 T 细胞随时间的表型和 TCR。