Understanding the impact of AAK1 on T cell chemokine receptor expression and chemotaxis

了解 AAK1 对 T 细胞趋化因子受体表达和趋化性的影响

• 批准号: 10300774
• 负责人: Laura Marie Rogers
• 金额: $ 23.85万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-08 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10300774
• 关键词: Adaptor Signaling Protein; Adoptive Transfer; Autoimmunity; Automobile Driving; Binding; Brain; CD8-Positive T-Lymphocytes; CXCL10 gene; CXCR3 gene; Cell surface; Cells; Cerebral Palsy; Chemotaxis; Clathrin; Data; Dementia; Development; Disease; Disease Progression; Endocytosis; Epilepsy; Evaluation; Flow Cytometry; Generations; Genetic; Genetic Screening; Goals; Hela Cells; Immune; Immune System Diseases; Impairment; In Vitro; Infection; Infiltration; Inflammatory; Knockout Mice; Lead; Ligands; Link; Malignant Neoplasms; Measures; Mediating; Migration Assay; Modeling; Molecular; Multiple Sclerosis; Mus; Neuraxis; Neurodegenerative Disorders; Neurons; Pathogenicity; Patients; Pharmacology; Phosphotransferases; Play; Protein Inhibition; Proteins; Receptor Signaling; Regulation; Role; Seizures; Severities; Signal Transduction; Symptoms; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; TMEV; Testing; Therapeutic; Tissues; Translating; Tumor Tissue; Tumor-infiltrating immune cells; Validation; Virus Diseases; Work; cell motility; chemokine; chemokine receptor; cytokine; design; disease phenotype; experimental study; high reward; high risk; immunogenic; in vivo; innovation; link protein; molecular domain; mouse model; mutant; neuroinflammation; new therapeutic target; novel; overexpression; prevent; receptor; receptor expression; receptor internalization; recruit; therapeutic target; trafficking; tumor

PROJECT SUMMARY/ABSTRACT T cells infiltrating into the brain directly and indirectly promote neuronal impairment in a wide variety of neuroinflammatory diseases, including dementia, multiple sclerosis (MS), and epilepsy. Thus, limiting T cell infiltration into the central nervous system could have therapeutic benefit for these patients. Adapter protein 2 associated kinase 1 (Aak1) was recently identified as an important regulator of T cell chemotaxis into inflamed tissues in an in vivo forward genetic screen. The primary objective of this project is to understand how AAK1 regulates T cell chemotaxis, with a secondary goal of establishing the translational potential of AAK1 as a therapeutic target in neuroinflammatory diseases. These goals will be accomplished in two aims. Aim 1 will determine if AAK1 regulates chemokine receptor expression on the T cell surface using primary T cells. Aim 2 will define the extent to which AAK1 regulates T cell chemotaxis using in vitro migration assays and in vivo T cell trafficking into the brain using the Theiler’s murine encephalomyelitis virus (TMEV) model of MS. This proposal has several innovative aspects, including generation of a novel, T cell specific Aak1 knockout mouse, validation of Aak1 as a genetic regulator of T cell infiltration, functional and mechanistic testing of a novel Aak1 mutant construct, and evaluation of Aak1 as a novel therapeutic target to limit T cell chemotaxis into inflamed tissue. Successful completion of this project will broadly benefit many disease settings, as findings can easily be translated to other inflammatory conditions where recruitment of T cells drives pathogenicity and may lead to better treatments of immunologic diseases.

项目概要/摘要 T 细胞直接或间接地渗入大脑，促进多种神经损伤 神经炎症疾病，包括痴呆、多发性硬化症 (MS) 和癫痫，因此限制了 T 细胞。 接头蛋白 2 渗入中枢神经系统可能具有治疗益处。 相关激酶 1 (Aak1) 最近被确定为 T 细胞趋化性炎症的重要调节因子 体内正向遗传筛选中的组织 该项目的主要目标是了解 AAK1 是如何发挥作用的。 调节 T 细胞趋化性，第二个目标是确定 AAK1 作为 T 细胞趋化性的翻译潜力 神经炎症疾病的治疗目标将通过两个目标来实现。 使用原代 T 细胞确定 AAK1 是否调节 T 细胞表面的趋化因子受体表达。 将使用体外迁移测定和体内 T 来定义 AAK1 调节 T 细胞趋化性的程度 使用多发性硬化症的泰勒鼠脑脊髓炎病毒 (TMEV) 模型将细胞贩运到大脑中。 该提案有几个创新方面，包括生成新型 T 细胞特异性 Aak1 敲除小鼠， 验证 Aak1 作为 T 细胞浸润的遗传调节因子，并对新型 Aak1 进行功能和机制测试 突变体构建，以及评估 Aak1 作为限制 T 细胞趋化进入炎症的新治疗靶点 该项目的成功完成将广泛有益于许多疾病环境，因为研究结果很容易得到。 被转化为其他炎症状况，其中 T 细胞的募集驱动致病性并可能导致 更好地治疗免疫性疾病。