STAT5 tetramerization in autoimmune-mediated neuroinflammation
自身免疫介导的神经炎症中的 STAT5 四聚化
基本信息
- 批准号:10627016
- 负责人:
- 金额:$ 26.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-06-07 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:Active ImmunizationAdoptive TransferAffinityAnimal ModelAntibodiesAntigen-Presenting CellsAutoimmuneBiological AssayBiological ProcessBlocking AntibodiesCCL17 geneCD4 Positive T LymphocytesCell CommunicationCellsComplexCytokine ActivationDemyelinationsDendritic CellsDiseaseExperimental Autoimmune EncephalomyelitisExtravasationFreund&aposs AdjuvantGene Expression ProfileGoalsGranulocyte-Macrophage Colony-Stimulating FactorGrowth FactorITGAX geneImaging TechniquesImmuneIn VitroInfiltrationInflammationIntegrin BindingIntegrinsInterferonsInterleukin-17Knock-inKnock-in MouseLeadMediatingMediator of activation proteinMeningealMeningesMonitorMouse StrainsMultiple SclerosisMusMyeloid CellsN DomainNeuraxisOnset of illnessPathogenesisPathogenicityPathway interactionsPersonsPhenotypePlayPopulationReporterRoleSignal PathwaySignal TransductionSpinal CordStat5 proteinTestingTumor-infiltrating immune cellsWorkaxonal degenerationcell typechemokinecytokinedimerearly onseteffective therapyin vivoinsightintravital imagingmacrophagemonocytemultiple sclerosis treatmentneuroinflammationnovelnovel strategiesresponseyoung adult
项目摘要
Project Summary/Abstract
Multiple sclerosis (MS) is an immune-mediated disease that impacts approximately 2.3 million people world-
wide. MS is caused by the activation and the complex interactions between different immune cell types that
cause inflammation in the central nervous system (CNS), which leads to demyelination and axonal degeneration.
A validated animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), has been
utilized to demonstrate that the cognate interactions between CD4+ T cells and monocyte-derived cells (MDCs),
defined here a mixed population of dendritic cells and macrophages differentiated from monocytes during the
autoimmune-driven neuroinflammation, are required for the pathogenesis of EAE. The overall goal of this
proposal is to identify signaling pathways and their downstream effector mediators that regulate the interactions
of CD4+ T cells and MDCs within CNS that promote the pathogenesis of EAE. Signal transducers and activators
of transcription 5A and 5B (STAT5A and STAT5B) play a critical role in mediating cellular responses following
stimulation of cytokines, interferons, growth factors. The activated STAT5 proteins can form dimers and
tetramers. The biological functions of STAT5 tetramers are not fully understood. Using a Stat5a-Stat5b N-domain
double knock-in (DKI) mouse strain, in which STAT5 tetramers cannot be formed but STAT5 dimers are
unaffected, we found that STAT5 tetramers promote the pathogenesis of EAE. The mild EAE phenotype in DKI
mice correlates with reduced interactions of CD4+ T cells and monocytes/MDCs in the spinal cord meninges
during EAE. We further demonstrated that STAT5 tetramer activation by cytokine GM-CSF promotes monocyte
differentiation into dendritic cells and the expression of chemokine CCL17. Correspondingly, the expression of
CCL17 in the spinal cords is significantly reduced in DKI mice during EAE. Importantly, mice receiving STAT5
tetramer-deficient Th17 cells treated with CCL17 developed more severe EAE with earlier onset of the disease
compared with mice receiving cells without CCL17 treatment. Our central hypothesis is that GM-CSF-mediated
STAT5 tetramerization is critical for facilitating the interactions of pathogenic Th17 cells and monocytes/MDCs
in the spinal cord meninges via a CCL17-dependent mechanism, and these cell interactions are required to
promote the pathogenesis of EAE. We will test our hypothesis in three specific aims. In Aim 1, we will utilize
different EAE induction strategies to determine the pathogenic role of STAT5 tetramers in CD4+ T cells and
monocytes/MDCs during EAE. In Aim 2, we will test our hypothesis that STAT5 tetramer signaling promotes
monocyte differentiation and Th17 cell-MDC interactions at the spinal cord meninges during EAE using intravital
imaging technique. In Aim 3, we will investigate the mechanism by which CCL17 promotes the pathogenesis of
EAE. Specifically, we will test our hypothesis that CCL17 increases the affinity of integrin LFA-1 on Th17 cells,
thereby facilitates Th17 cell-MDC interactions. Targeting the pathways and mediators that control the interactions
between CD4+ T cells and MDCs within CNS may become a novel strategy for the treatments of MS.
项目总结/文摘
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 }}
EDWIN CHI KEUNG WAN其他文献
EDWIN CHI KEUNG WAN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('EDWIN CHI KEUNG WAN', 18)}}的其他基金
The role of CD11c+ microglia in post-ischemic stroke recovery
CD11c小胶质细胞在缺血性中风后恢复中的作用
- 批准号:
10542785 - 财政年份:2022
- 资助金额:
$ 26.6万 - 项目类别:
The role of CD11c+ microglia in post-ischemic stroke recovery
CD11c小胶质细胞在缺血性中风后恢复中的作用
- 批准号:
10350461 - 财政年份:2022
- 资助金额:
$ 26.6万 - 项目类别:
Mechanistic Study of Stroke-induced Immune Suppression and Identification of Immune Modulatory Targets for Stroke-associated Pneumonia
中风引起的免疫抑制机制研究及中风相关肺炎免疫调节靶点的鉴定
- 批准号:
10217167 - 财政年份:2014
- 资助金额:
$ 26.6万 - 项目类别:
Mechanistic Study of Stroke-induced Immune Suppression and Identification of Immune Modulatory Targets for Stroke-associated Pneumonia
中风引起的免疫抑制机制研究及中风相关肺炎免疫调节靶点的鉴定
- 批准号:
10025933 - 财政年份:2014
- 资助金额:
$ 26.6万 - 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:
$ 26.6万 - 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:
$ 26.6万 - 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:
$ 26.6万 - 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:
$ 26.6万 - 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:
$ 26.6万 - 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:
$ 26.6万 - 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:
$ 26.6万 - 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:
$ 26.6万 - 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:
$ 26.6万 - 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:
$ 26.6万 - 项目类别:














{{item.name}}会员




