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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.

项目摘要/摘要 T细胞直接或间接地渗入脑内可促进多种神经细胞损伤神经炎症性疾病，包括痴呆症、多发性硬化症(MS)和癫痫。因此，限制T细胞向中枢神经系统的渗透可能对这些患者有治疗益处。接头蛋白2 相关蛋白1(Aak1)是近年来发现的一种重要的T细胞趋化因子体内正向遗传筛查中的组织。这个项目的主要目标是了解AAK1是如何调节T细胞的趋化性，次要目标是建立AAK1的翻译潜力作为一种神经炎症性疾病的治疗靶点。这些目标将通过两个目标实现。目标1将确定AAK1是否利用原代T细胞调节T细胞表面趋化因子受体的表达。目标2 将使用体外迁移试验和体内T细胞迁移试验确定AAK1调节T细胞趋化的程度使用MS的泰勒小鼠脑脊髓炎病毒(TMEV)模型将细胞转运到脑中该提议有几个创新方面，包括产生一种新型的T细胞特异性Aak1基因敲除小鼠， Aak1作为T细胞渗透的遗传调节因子的验证及其功能和机制测试突变型构建及Aak1作为限制炎性T细胞趋化作用新靶点的研究组织。这一项目的成功完成将使许多疾病环境广泛受益，因为研究结果很容易转化为其他炎症状态，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。