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:
  • 金额:
    $ 23.85万
  • 依托单位:
  • 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

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。

项目成果

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Laura Marie Rogers其他文献

Laura Marie Rogers的其他文献

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{{ truncateString('Laura Marie Rogers', 18)}}的其他基金

Aak1 to increase infiltration of adoptively transferred cells into solid tumors
Aak1 增加过继转移细胞向实体瘤的浸润
  • 批准号:
    10558244
  • 财政年份:
    2023
  • 资助金额:
    $ 23.85万
  • 项目类别:
Rationally improving T cell-mediated immunotherapy using Sleeping Beauty mutagenesis
利用睡美人诱变合理改进 T 细胞介导的免疫治疗
  • 批准号:
    10238780
  • 财政年份:
    2019
  • 资助金额:
    $ 23.85万
  • 项目类别:
Rationally improving T cell-mediated immunotherapy using Sleeping Beauty mutagenesis
利用睡美人诱变合理改进 T 细胞介导的免疫治疗
  • 批准号:
    9503289
  • 财政年份:
    2019
  • 资助金额:
    $ 23.85万
  • 项目类别:

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