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.

摘要 类风湿性关节炎（RA）是一种全身性自身免疫性疾病，其特征在于 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还不清楚。为了回答这个问题，我们决定调查 趋化因子受体在浸润性T细胞上的表达。趋化因子受体是跨膜蛋白 受体，其促进免疫细胞朝向其各自细胞因子的梯度迁移。以前的工作 实验室发现，在发炎的滑膜中有大量的T细胞表达趋化因子受体CCR2。在 此外，其他研究组的工作一致显示，在RA患者中CCR2表达升高， 然而，在血液中，还没有对RA中CCR 2的T细胞特异性损失的研究。此外，本发明还 趋化因子受体通常用作鉴定辅助T细胞的功能亚群的标记物。考虑 炎症滑膜中有大量表达CCR2的T细胞，我们假设CCR2可能 促进炎症滑膜内的迁移或定位，并可划分功能性T细胞 人口此外，关于T细胞上CCR2表达的调节知之甚少，更好的是， 理解其调节可以允许调节所提议的迁移或功能性编程。 因此，我们提出了一个强有力的调查，在T细胞中的CCR2的调节和功能，利用 细胞计数、转录组学、功能和鼠系统，以彻底表征该人群， 了解其在RA发病机制中的作用。