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
- 来源:
- 关键词:Adaptor Signaling ProteinAdoptive TransferAutoimmunityAutomobile DrivingBindingBrainCD8-Positive T-LymphocytesCXCL10 geneCXCR3 geneCell surfaceCellsCerebral PalsyChemotaxisClathrinDataDementiaDevelopmentDiseaseDisease ProgressionEndocytosisEpilepsyEvaluationFlow CytometryGenerationsGeneticGenetic ScreeningGoalsHela CellsImmuneImmune System DiseasesImpairmentIn VitroInfectionInfiltrationInflammatoryKnockout MiceLeadLigandsLinkMalignant NeoplasmsMeasuresMediatingMigration AssayModelingMolecularMultiple SclerosisMusNeuraxisNeurodegenerative DisordersNeuronsPathogenicityPatientsPharmacologyPhosphotransferasesPlayProtein InhibitionProteinsReceptor SignalingRegulationRoleSeizuresSeveritiesSignal TransductionSymptomsT cell responseT-LymphocyteT-Lymphocyte SubsetsTMEVTestingTherapeuticTissuesTranslatingTumor TissueTumor-infiltrating immune cellsValidationVirus DiseasesWorkcell motilitychemokinechemokine receptorcytokinedesigndisease phenotypeexperimental studyhigh rewardhigh riskimmunogenicin vivoinnovationlink proteinmolecular domainmouse modelmutantneuroinflammationnew therapeutic targetnoveloverexpressionpreventreceptorreceptor expressionreceptor internalizationrecruittherapeutic targettraffickingtumor
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
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Laura Marie Rogers其他文献
Laura Marie Rogers的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似海外基金
Time to ATTAC: Adoptive Transfer of T cells Against gp100+ Cells to treat LAM
ATTAC 时间:针对 gp100 细胞的 T 细胞过继转移来治疗 LAM
- 批准号:
10682121 - 财政年份:2023
- 资助金额:
$ 23.85万 - 项目类别:
Phase I clinical trial of adoptive transfer of autologous folate receptor-alpha redirected CAR T cells for ovarian cancer
自体叶酸受体-α重定向CAR T细胞过继转移治疗卵巢癌的I期临床试验
- 批准号:
10576370 - 财政年份:2022
- 资助金额:
$ 23.85万 - 项目类别:
Phase I clinical trial of adoptive transfer of autologous folate receptor-alpha redirected CAR T cells for ovarian cancer
自体叶酸受体-α重定向CAR T细胞过继转移治疗卵巢癌的I期临床试验
- 批准号:
10387023 - 财政年份:2022
- 资助金额:
$ 23.85万 - 项目类别:
Determining mechanisms of enhanced antitumor efficacy of four-day expanded Th17 cells for adoptive transfer
确定用于过继转移的四天扩增 Th17 细胞增强抗肿瘤功效的机制
- 批准号:
10248409 - 财政年份:2019
- 资助金额:
$ 23.85万 - 项目类别:
A phase I clinical study of adoptive transfer of regulatory T cells (Tregs) and low-dose interleukin-2 (IL-2) for the treatment of chronic graft-versus-host disease (GVHD): gene-marking to inform rational combination therapy
调节性 T 细胞 (Treg) 和低剂量白细胞介素 2 (IL-2) 过继转移治疗慢性移植物抗宿主病 (GVHD) 的 I 期临床研究:基因标记为合理的联合治疗提供信息
- 批准号:
nhmrc : GNT1163111 - 财政年份:2019
- 资助金额:
$ 23.85万 - 项目类别:
Project Grants
Determining mechanisms of enhanced antitumor efficacy of four-day expanded Th17 cells for adoptive transfer
确定用于过继转移的四天扩增 Th17 细胞增强抗肿瘤功效的机制
- 批准号:
10462684 - 财政年份:2019
- 资助金额:
$ 23.85万 - 项目类别:
Gene edited lymphoid progenitors for adoptive transfer as a treatment of primary immunodeficiency
基因编辑的淋巴祖细胞用于过继转移作为原发性免疫缺陷的治疗
- 批准号:
398018062 - 财政年份:2018
- 资助金额:
$ 23.85万 - 项目类别:
Research Grants
Overcoming immune suppression in cancer by targeting PSGL-1 in T cells used for adoptive transfer
通过靶向用于过继转移的 T 细胞中的 PSGL-1 克服癌症中的免疫抑制
- 批准号:
9308643 - 财政年份:2017
- 资助金额:
$ 23.85万 - 项目类别:
Overcoming immune suppression in cancer by targeting PSGL-1 in T cells used for adoptive transfer
通过靶向用于过继转移的 T 细胞中的 PSGL-1 克服癌症中的免疫抑制
- 批准号:
9447149 - 财政年份:2017
- 资助金额:
$ 23.85万 - 项目类别:
Targeting Cancer miRNAs by Adoptive Transfer of Programmed B Lymphocytes
通过程序化 B 淋巴细胞的过继转移靶向癌症 miRNA
- 批准号:
8893915 - 财政年份:2014
- 资助金额:
$ 23.85万 - 项目类别: