Regulation and function of CCR2 on T cells in Rheumatoid Arthritis

CCR2对类风湿性关节炎T细胞的调控及功能

• 批准号: 10672641
• 负责人: Sabrina Esmeralda Bracero
• 金额: $ 4.17万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672641
• 关键词: ATAC-seq; Affect; Area; Autoimmune Diseases; Automobile Driving; Bioinformatics; Biometry; Blood; Bone Marrow; CCL2 gene; CD4 Positive T Lymphocytes; CRISPR screen; Cartilage; Cells; Chimera organism; Chronic; Collagen Arthritis; Data; Dedications; Development; Disease; Environment; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Genes; Genetic Transcription; Goals; Helper-Inducer T-Lymphocyte; Heterogeneity; Human; Immune; Immunohistochemistry; Immunology; Infiltration; Inflammatory; Inflammatory Arthritis; Integral Membrane Protein; Investigation; Joints; Knock-out; Laboratory Finding; Lymphocyte Biology; Macrophage; Memory; Mentors; Modeling; Mononuclear; Mus; Myeloid Cells; Pathogenesis; Pathology; Patients; Peripheral Blood Mononuclear Cell; Persons; Population; Positioning Attribute; Production; Regulation; Research; Research Personnel; Rheumatoid Arthritis; Role; Synovial Fluid; Synovitis; System; T cell infiltration; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic; United States; Work; bone; candidate identification; cell motility; chemokine; chemokine receptor; cytokine; experience; joint inflammation; migration; monocyte chemoattractant protein 1 receptor; mouse model; multiplex assay; programs; promoter; receptor; recruit; skills; systemic autoimmune disease; tool; transcription factor; transcriptome; transcriptome sequencing; transcriptomics

Abstract Rheumatoid Arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of the synovium and infiltration of mononuclear cells into the joint. Once in the joint the mononuclear cells, predominantly T cells and macrophages, contribute significantly to disease pathology, yet the mechanism by which these cells enter the joint is not clearly established. To answer this question, we decided to investigate the expression of chemokine receptors on infiltrating T cells. Chemokine receptors are transmembrane protein receptors that facilitate immune cell migration towards gradients of their respective cytokines. Previous work in the lab found a large population of T cells in the inflamed synovium express the chemokine receptor CCR2. In addition, work from other groups have consistently shown an elevated expression of CCR2 in RA patient blood, however, there have not been investigations into T cell specific loss of CCR2 in RA. Additionally, chemokine receptors are often used as markers to identify functional subsets of helper T cells. Considering the robust population of T cells expressing CCR2 in the inflamed synovium, we hypothesized that CCR2 may facilitate migration or positioning within the inflamed synovium and may demarcate a functional T cell population. Furthermore, very little is known about the regulation of CCR2 expression on T cells and better understanding of its regulation could allow for modulation of the proposed migratory or functional programming. Therefore, we are proposing a robust investigation into the regulation and function of CCR2 in T cells utilizing cytometric, transcriptomic, functional, and murine systems to thoroughly characterize this population and better understand its role in RA pathogenesis.

抽象的 类风湿性关节炎（RA）是一种全身性自身免疫性疾病，其特征是关节慢性炎症 滑膜和单核细胞浸润到关节中。一旦单核细胞进入关节， 主要是 T 细胞和巨噬细胞，对疾病病理学有显着贡献，但其机制是 这些细胞进入关节的方式尚不清楚。为了回答这个问题，我们决定调查一下 浸润性 T 细胞上趋化因子受体的表达。趋化因子受体是跨膜蛋白 促进免疫细胞向各自细胞因子梯度迁移的受体。之前的工作于 实验室发现发炎滑膜中有大量 T 细胞表达趋化因子受体 CCR2。在 此外，其他小组的工作一致表明 RA 患者中 CCR2 的表达升高 然而，尚未对 RA 中 T 细胞特异性 CCR2 缺失进行研究。此外， 趋化因子受体通常用作识别辅助 T 细胞功能亚群的标记。考虑到 在发炎的滑膜中存在大量表达 CCR2 的 T 细胞，我们假设 CCR2 可能 促进发炎滑膜内的迁移或定位，并可能界定功能性 T 细胞 人口。此外，对于 T 细胞上 CCR2 表达的调节知之甚少，更好的是 了解其监管可以允许调整拟议的迁移或功能规划。 因此，我们建议利用 T 细胞中的 CCR2 调节和功能进行强有力的研究 细胞计数、转录组、功能和小鼠系统，以彻底表征该群体并更好地 了解其在 RA 发病机制中的作用。