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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/摘要 T细胞直接和间接地浸润到大脑中，在各种各样的神经元损伤中促进神经元损伤。神经炎性疾病，包括痴呆、多发性硬化（MS）和癫痫。因此，限制T细胞浸润到中枢神经系统可能对这些患者具有治疗益处。衔接蛋白2 相关激酶1（Aak 1）最近被鉴定为T细胞趋化性进入炎症的重要调节因子，在体内正向遗传筛选中的组织。本项目的主要目标是了解AAK 1 调节T细胞的趋化性，次要目标是建立AAK 1的翻译潜力，神经炎性疾病的治疗靶点。这些目标将通过两个目标来实现。目标1将使用原代T细胞确定AAK 1是否调节T细胞表面上的趋化因子受体表达。目的2 将使用体外迁移测定和体内T细胞趋化性测定来确定AAK 1调节T细胞趋化性的程度。使用MS的Theiler小鼠脑脊髓炎病毒（TMEV）模型将细胞运输到脑中。该提案具有几个创新方面，包括产生新的T细胞特异性Aak 1敲除小鼠， Aak 1作为T细胞浸润的遗传调节剂的验证，新型Aak 1的功能和机制测试 Aak 1作为限制T细胞趋化性进入炎症的新的治疗靶点的评价组织.该项目的成功完成将使许多疾病环境广泛受益，因为研究结果可以很容易地翻译为其他炎症性疾病，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