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

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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