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.

项目摘要/摘要 T细胞直接和间接地浸入大脑中 神经炎症性疾病，包括痴呆，多发性硬化症（MS）和癫痫病。那限制了T细胞 中枢神经系统的渗透可能对这些患者具有治疗益处。衔接蛋白2 最近将相关的激酶1（AAK1）确定为T细胞趋化性的重要调节剂发炎 体内正向遗传筛查中的组织。该项目的主要目的是了解AAK1如何 调节T细胞趋化性，其次要目标是建立AAK1的翻译潜力 神经炎症性疾病的治疗靶标。这些目标将以两个目标实现。目标1意志 确定AAK1是否使用原代T细胞在T细胞表面调节趋化因子受体的表达。目标2 将定义AAK1使用体外迁移测定和体内T的调节T细胞趋化性的程度 使用Theiler的鼠类脑脊髓炎病毒（TMEV）模型，将细胞运输到大脑中。这 提案具有几个创新方面 验证AAK1作为T细胞浸润的遗传调节剂，新型AAK1的功能和机械测试 突变构建体，以及将AAK1作为一种新型治疗靶标的评估，以将T细胞趋化性限制在发炎中 组织。成功完成该项目将广泛受益于许多疾病环境，因为发现很容易 将T细胞募集驱动致病性并可能导致的其他炎症条件转化为其他炎症条件 更好地治疗免疫疾病。