Mechanisms by which PIM kinase modulates the effector function of autoreactive CD8 T cells in type 1 diabetes

PIM 激酶调节 1 型糖尿病自身反应性 CD8 T 细胞效应功能的机制

基本信息

批准号：
10605431
负责人：
Ashley K Brown
金额：
$ 5.27万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-07 至 2027-04-06
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10605431
关键词：
Acceleration Affect Algorithms Autoimmune Autoimmune Diabetes Autoimmune Diseases B-Lymphocytes Beta Cell Biochemical Pathway Bioenergetics Bioinformatics Blood CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CRISPR/Cas technology Cell Compartmentation Cell Cycle Progression Cell Separation Cell Survival Cell physiology Cellular Metabolic Process Childhood diabetes Clinical Complement Cytotoxic T-Lymphocytes Data Dependence Development Diabetes Mellitus Disease Family Fellowship Financial Hardship Genes Genetic Transcription Glucose Goals Histology Immunologics Immunology In Vitro Inbred NOD Mice Incidence Infiltration Inflammation Mediators Insulin Insulin deficiency Insulin-Dependent Diabetes Mellitus Knock-out Knowledge Manuscripts Measures Mediating Metabolic Metabolism Mission Mitochondria Molecular Moloney Leukemia Virus Morphology Mus National Institute of Diabetes and Digestive and Kidney Diseases Non obese Oxidative Stress PIM1 gene Pathway interactions Phenotype Phosphorylation Phosphotransferases Physicians Prevention Process Production Protein-Serine-Threonine Kinases Provirus Integration Publications Rag1 Mouse Research Research Institute Risk Role Scientist Severities Signal Transduction Structure Structure of beta Cell of islet T cell therapy T-Cell Activation T-Lymphocyte Testing Time Training United States Urine Wisconsin autoreactive B cell autoreactivity body system cell growth chronic autoimmune disease clinically relevant cytokine diabetic diabetogenic effector T cell experimental study insulin dependent diabetes mellitus onset integration site interleukin-21 islet kinase inhibitor medical schools meetings metabolic profile mouse model multidisciplinary new therapeutic target overexpression pharmacologic prevent proto-oncogene protein pim single-cell RNA sequencing transcriptomics young adult

项目摘要

Project Summary Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by T cell destruction of insulin- producing pancreatic b cells. This results in lifelong dependence on exogenous insulin therapy and increases the risk of complications in many organ systems. Advances in understanding the mechanisms by which T cells mediate their autoimmune functions may provide new therapeutic targets for T1D. It is established that CD4 T cells and CD8 T cells are both required for the development of T1D. Studies found that the cytokine IL-21 functions as a critical signal produced by CD4 T cells to help CD8 T cells destroy insulin-producing b cells. However, the direct effects of IL-21 on β cell-reactive CD8 T cell effector function remain incompletely understood. Therefore, the long-term goal of this project is to elucidate molecular mechanisms regulating autoreactive CD8 T cell function. Preliminary scRNA-seq data presented in this proposal identified Pim1 as a possible modulator of activated diabetogenic CD8 T cell function. PIM1 belongs to a serine/threonine protein kinase family that functions downstream of the JAK-STAT pathway and is involved in regulating many processes including cell survival and metabolism. It was also demonstrated that IL-21 induced the expression of PIM1 and its downstream targets in CD8 T cells, while inhibition of PIM kinase in the presence of IL-21 resulted in reduced expression of PIM1 downstream targets. These data led to the hypothesis that IL-21-induced PIM1 kinase is necessary for supporting the sustained cytolytic function and metabolic demands of autoreactive CD8 T cells that are required for T1D development. Aim 1 will determine the role of PIM1 kinase in β cell-autoreactive CD8 T cell cytolytic function in T1D development. These experiments will determine if PIM1 is necessary and sufficient for T1D development. Additionally, the immunological phenotype of autoreactive CD8 T cells following inhibition and overexpression of PIM1 will be assessed. Aim 2 will elucidate the role of PIM1 kinase in b cell- autoreactive CD8 T cell signal transduction and metabolism in T1D. This project will be conducted at the Medical College of Wisconsin and Versiti Blood Research Institute with multidisciplinary support from experts in immunology and diabetes. Rigorous research and bioinformatic training in addition to presentations at national meetings and publication of manuscripts in immunology and T1D will support the development of an independent, academic physician-scientist. Overall, this proposal will advance knowledge of how b cell-autoreactive CD8 T cells function during the development of T1D. This is in line with the mission of NIDDK, since the results of this project may identify PIM1 as a novel therapeutic target for T1D.

项目概要 1 型糖尿病 (T1D) 是一种慢性自身免疫性疾病，其特征是 T 细胞破坏胰岛素- 产生胰腺 b 细胞，这导致终生依赖外源性胰岛素治疗和增加了许多器官系统并发症的风险。 T细胞介导自身免疫功能的机制可能提供新的治疗靶点对于 T1D，已确定 CD4 T 细胞和 CD8 T 细胞都是 T1D 发育所必需的。研究发现细胞因子 IL-21 作为 CD4 T 细胞产生的关键信号发挥作用，以帮助 CD8 T 细胞破坏产生胰岛素的 b 细胞，但 IL-21 对 β 细胞反应性有直接影响。 CD8 T 细胞效应功能仍不完全清楚，因此该研究的长期目标。该项目旨在阐明调节自身反应性 CD8 T 细胞功能的分子机制。该提案中提供的初步 scRNA-seq 数据确定 Pim1 是一种可能的调节剂激活的致糖尿病 CD8 T 细胞功能 PIM1 属于丝氨酸/苏氨酸蛋白激酶家族。在 JAK-STAT 通路下游发挥作用并参与调节许多过程包括细胞存活和代谢也被证明IL-21诱导表达。 PIM1 及其下游 CD8 T 细胞靶标，同时在 IL-21 存在的情况下抑制 PIM 激酶导致 PIM1 下游靶标的表达减少。这些数据导致了这样的假设： IL-21 诱导的 PIM1 激酶对于支持持续的细胞溶解功能和 T1D 发展所需的自身反应性 CD8 T 细胞的代谢需求将达到目标 1。确定 PIM1 激酶在 T1D β 细胞自身反应性 CD8 T 细胞溶细胞功能中的作用这些实验将确定 PIM1 对于 T1D 是否是必要且充分的。此外，抑制后自身反应性 CD8 T 细胞的免疫表型。将评估 PIM1 的过度表达，目标 2 将阐明 PIM1 激酶在 b 细胞中的作用。 T1D 中的自身反应性 CD8 T 细胞信号转导和代谢将进行。在威斯康星医学院和 Versiti 血液研究所获得多学科支持除了来自免疫学和糖尿病专家的严格研究和生物信息培训。在全国会议上的演讲以及免疫学和 T1D 手稿的出版将支持总体而言，该提案将促进独立的学术医师科学家的发展。了解 b 细胞自身反应性 CD8 T 细胞在 T1D 发展过程中如何发挥作用。符合 NIDDK 的使命，因为该项目的结果可能会将 PIM1 视为一种新颖的 T1D 的治疗目标。