Mechanistic study of TCR signaling strength in CD8 T cell differentiation during pathogenesis of T1DM

T1DM发病过程中CD8 T细胞分化的TCR信号强度机制研究

基本信息

批准号：
10255502
负责人：
Moujtaba Y Kasmani
金额：
$ 5.1万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-03 至 2024-09-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10255502
关键词：
Address Adverse effects Affect Affinity Algorithms American Amino Acids Autoimmune Diseases Beta Cell Binding Blood Blood Glucose CD8-Positive T-Lymphocytes Cell Differentiation process Cells Chronic Clinical Research Computer Analysis Computer Models Data Data Analyses Dendritic Cells Dependence Development Disease Fellowship G6PC2 gene Goals Growth Heterogeneity Immune Immunologist Immunology Immunotherapy In Vitro Inbred NOD Mice Individual Inflammatory Institution Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Knowledge Lead Left Letters Ligands Major Histocompatibility Complex Malignant Neoplasms Manuscripts Maps Mediating Mentors Mentorship Methods Mission Modeling Mus Mutate Mutation National Institute of Diabetes and Digestive and Kidney Diseases Parents Pathogenesis Pathologic Patients Peptide Receptor Peptides Phase II Clinical Trials Phenotype Physicians Physiologic pulse Physiological Process Property Publishing RNA Receptor Signaling Research Research Institute Role Scientist Signal Transduction Structure of beta Cell of islet T cell differentiation T cell receptor repertoire sequencing T-Cell Antigen Receptor Specificity T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Time Training Virus Diseases Wisconsin Work Writing autoimmune pathogenesis chronic infection clinically relevant diabetogenic exhaust exhaustion experimental study high risk immunomodulatory therapies immunopathology improved in vivo insulin dependent diabetes mellitus onset medical schools meetings multidisciplinary progenitor self-renewal single-cell RNA sequencing stem cells transcriptomics

项目摘要

Project Summary Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by CD8 T cell-mediated destruction of pancreatic beta cells. This leads to an inability to produce insulin and thus a lifelong dependence on exogenous insulin, as is the case for over 1 million Americans. A recent phase II clinical trial has shown it is possible to delay the time to onset of T1DM using a non-specific immunotherapy that promotes signaling through the T cell receptor (TCR) to induce a state of T cell exhaustion. Recent studies have shown that CD8 T cells in chronic infection and cancer are heterogeneous, consisting of self-renewing progenitor cells that give rise to both cytolytic effector and non-cytolytic exhausted cells. However, CD8 T cell heterogeneity in T1DM and the processes connecting TCR signaling and CD8 T cell differentiation are not yet fully understood. A better understanding of these concepts is vital for developing more specific immunotherapies for T1DM. Therefore, the overarching goal of this fellowship is to investigate the mechanisms by which TCR signaling affects CD8 T cell differentiation in T1DM. Aim 1 will map the phenotypic, clonal, and energetic landscapes of diabetogenic CD8 T cells. Aim 2 will investigate whether diabetogenic CD8 T cells can be selectively exhausted via exogenous TCR stimulation. This project addresses knowledge gaps at the intersection of immunology and T1DM research in order to obtain a better understanding of the role of CD8 T cells in the pathogenesis of T1DM. This work will further scientific and clinical studies that aim to delay the onset of T1DM in a more selective manner with fewer immunosuppressive adverse effects. This project will be conducted at the Medical College of Wisconsin and the Versiti Wisconsin Blood Research Institute with the mentorship of 6 immunologists and biochemists to provide multidisciplinary fellowship training. These mentors and institutions will provide excellent training in the form of rigorous hands-on experiments, insightful data analysis, focused manuscript writing when publishing results, and attendance at local and national meetings in the fields of immunology and T1DM. The results of this fellowship could lead to an improved understanding of how fundamental mechanisms of CD8 T cell signaling and differentiation impact the immunopathology and disease course of T1DM, in line with the mission of NIDDK.

项目摘要 1型糖尿病（T1DM）是一种以CD8 T细胞介导的破坏为特征的自身免疫性疾病胰腺β细胞。这导致无法产生胰岛素，从而终生依赖外源性胰岛素，就像超过100万美国人一样。最近的II期临床试验表明，有可能延迟使用非特异性免疫疗法促进通过T细胞信号传导的T1DM发作的时间受体（TCR）诱导T细胞耗尽的状态。最近的研究表明，慢性的CD8 T细胞感染和癌症是异质的，由自我更新的祖细胞组成，这两者都会引起两者细胞溶解效应子和非溶解的细胞。但是，T1DM中的CD8 T细胞异质性和连接TCR信号传导和CD8 T细胞分化的过程尚未完全了解。更好对这些概念的理解对于开发更具体的T1DM免疫疗法至关重要。所以，该团契的总体目标是研究TCR信号影响的机制 T1DM中的CD8 T细胞分化。 AIM 1将绘制表型，克隆和充满活力的景观糖尿病性CD8 T细胞。 AIM 2将研究是否可以选择性地研究糖尿病性CD8 T细胞通过外源性TCR刺激耗尽。该项目解决了在交集中的知识差距免疫学和T1DM研究，以便更好地了解CD8 T细胞在 T1DM的发病机理。这项工作将进一步科学和临床研究，旨在延迟T1DM的发作以更有选择性的方式具有更少的免疫抑制不良反应。该项目将在威斯康星州医学院和威斯康星州血液研究所的指导6 免疫学家和生物化学家提供多学科奖学金培训。这些导师和机构将以严格的动手实验，有见地的数据分析的形式提供出色的培训出版结果时的手稿写作，以及参加该领域的本地和国家会议免疫学和T1DM。该奖学金的结果可能会提高人们对 CD8 T细胞信号传导和分化的基本机制影响免疫病理学和 T1DM的疾病课程，符合NIDDK的任务。