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

• 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
• 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

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.

项目摘要 1型糖尿病（T1 D）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。这导致终身依赖外源性胰岛素治疗， 增加了许多器官系统并发症的风险。在了解 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T1 D。已经确定，CD 4 T细胞和CD 8 T细胞都是肿瘤发生所必需的。 T1D研究发现，细胞因子IL-21作为CD 4 T细胞产生的关键信号， CD 8 T细胞破坏产生胰岛素的B细胞。然而，IL-21对β细胞反应性细胞因子的直接作用是不明显的。 CD 8 T细胞效应子功能仍然不完全清楚。因此，这一长期目标 该项目旨在阐明调节自身反应性CD 8 T细胞功能的分子机制。 该提案中提出的初步scRNA-seq数据将Pim 1鉴定为可能的调节剂， 激活致糖尿病CD 8 T细胞功能。PIM 1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，参与调节许多过程 包括细胞存活和新陈代谢。还证明IL-21诱导了 PIM 1及其下游靶点在CD 8 T细胞中，同时在IL-21存在下抑制PIM激酶 导致PIM 1下游靶标的表达减少。这些数据导致了一个假设， IL-21诱导的PIM 1激酶对于支持持续的细胞溶解功能是必需的， T1 D发展所需的自身反应性CD 8 T细胞的代谢需求。目标1将 确定PIM 1激酶在T1 D患者β细胞自身反应性CD 8 T细胞细胞溶解功能中的作用 发展这些实验将确定PIM 1是否是T1 D的必要和充分条件。 发展此外，抑制后自身反应性CD 8 T细胞的免疫表型 并评估PIM 1的过表达。目的2阐明PIM 1激酶在B细胞中的作用。 T1 D中自身反应性CD 8 T细胞信号转导和代谢。该项目将在 在威斯康星州医学院和Versiti血液研究所， 来自免疫学和糖尿病专家。严格的研究和生物信息学培训， 在国家会议上的发言和免疫学和T1 D方面的手稿出版将支持 一个独立的，学术的物理学家科学家的发展。总的来说，这项提案将推动 了解B细胞自身反应性CD 8 T细胞在T1 D发展过程中的功能。这是 符合NIDDK的使命，因为该项目的结果可能会将PIM 1确定为一种新的 T1 D的治疗目标。