Inflammation resolution, neuroprotection, and brain repair to promote stroke recovery

炎症消解、神经保护和大脑修复以促进中风康复

基本信息

  • 批准号:
    9471926
  • 负责人:
  • 金额:
    $ 40.75万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-08-15 至 2022-05-31
  • 项目状态:
    已结题

项目摘要

Accumulating evidence implicates inflammation and immune responses in the pathophysiology of stroke. Immunomodulation has therefore emerged as a promising therapy for stroke. Regulatory lymphocytes, including CD4+CD25+ regulatory T cells (CD4+ Treg) and IL-10+ regulatory B cells (Bregs) are established modulators of immune responses in the injured brain. We recently discovered that another specialized T cell subpopulation—the CD8+CD122+CD49dhigh regulatory T cell—is among the first to enter the ischemic brain, even preceding the infiltration of CD4+ Tregs and Bregs. The primary function of CD8+ Tregs is to modulate the activities of other immune cells, especially effector T lymphocytes, and to maintain immune homeostasis. We found that selective depletion of circulating CD8+ Tregs exacerbated brain injury and functional outcomes at 3 and 7 days after stroke, and this could be reversed by the reconstitution of CD8+ Tregs. These exciting results suggest that CD8+ Tregs are natural defenders against ischemic brain injury. Further pilot studies discovered that: 1) CD8+ Treg-afforded early protection relies on their infiltration into the ischemic brain, as CD8+ Tregs lacking the “brain targeting signal” CXCR3 do not infiltrate into the ischemic brain and lose their capacity to reduce brain infarction in CD8+ Treg-depleted mice. 2) The infiltrated CD8+ Tregs undergo genomic reprogramming upon brain infiltration and transcriptional upregulation of a group of genes that possess inflammation-resolving and/or neurorestorative functions, including the leukemia inhibitory factor (LIF) receptor and epidermal growth factor-like transforming growth factor (ETGF). 3) Post-stroke adoptive transfer of CD8+ Tregs significantly reduces brain infarct, enhances white matter integrity, and improves neurological functions up to 14d after tMCAO. 4) Adoptive transfer of ETGF-deficient CD8+ Treg fails to protect against tMCAO. The current proposal will further explore the effects of CD8+ Tregs in ischemic stroke and develop CD8+ Treg adoptive transfer as an immune therapeutic therapy for stroke. The novel central hypothesis to be tested is that brain infiltration of CD8+ Tregs promotes long-term neurological recovery after stroke through LIF/LIFR/ETGF-mediated neuroprotection, resolution of neuroinflammation, and neurorestorative mechanisms. Three specific aims are proposed. Aim 1. Establish post-stroke adoptive transfer of CD8+ Tregs as a clinically relevant treatment against acute ischemic brain infarct. Aim 2. Test the hypothesis that post-stroke adoptive transfer of CD8+ Tregs promotes long-term neurological recovery and neurorestoration after ischemic stroke. Aim 3. Test the hypothesis that LIF/LIFR-mediated release of ETGF is essential for CD8+ Treg-afforded neuroprotection and neurorestoration. This study will be the first to rigorously investigate the role of CD8+ Tregs in ischemic brain injury. The results will improve our understanding of stroke immunomodulation and shed light on CD8+ Treg transfer as a potential therapeutic strategy.
越来越多的证据表明,炎症和免疫反应在炎症的病理生理学中起着重要作用。 中风因此,免疫调节已成为一种有前途的治疗中风。监管 淋巴细胞,包括CD 4 + CD 25+调节性T细胞(CD 4 + Treg)和IL-10+调节性B细胞(BCRs), 在受伤的大脑中建立了免疫反应的调节器。我们最近发现另一个 一种特殊的T细胞亚群--CD 8 + CD 122 + CD 49 dhigh调节性T细胞--是最早进入免疫系统的细胞之一。 缺血脑组织中CD 4 + T淋巴细胞和Bcl-2的浸润早于缺血脑组织中的T淋巴细胞和Bcl-2的浸润。CD 8+的主要功能 T淋巴细胞是调节其他免疫细胞,特别是效应T淋巴细胞的活动,并维持 免疫稳态我们发现循环中CD 8 + T淋巴细胞的选择性耗竭会加重脑损伤, 在中风后3天和7天的功能结果,这可以通过重建 CD 8 + T细胞。这些令人兴奋的结果表明,CD 8 + T细胞是缺血性脑损伤的天然防御者。 损伤进一步的初步研究发现:1)CD 8 + Treg的早期保护作用依赖于其浸润 由于缺乏“脑靶向信号”CXCR 3的CD 8 + T细胞不能浸润到缺血性脑中, 在CD 8 + Treg缺失小鼠中,它们可以减少缺血性脑并失去减少脑梗死的能力。2)的 浸润的CD 8 + T细胞在脑浸润和转录后经历基因组重编程 上调一组具有炎症消退和/或神经恢复功能的基因, 包括白血病抑制因子(LIF)受体和表皮生长因子样转化生长因子 因子(ETGF)。3)脑卒中后过继转移CD 8 + T细胞显著减少脑梗死, 白色物质的完整性,并改善神经功能长达14天后tMCAO。4)的过继转移 ETGF缺陷型CD 8 + Treg不能保护tMCAO。目前的建议将进一步探讨 CD 8 + Treg过继转移作为免疫治疗方法 治疗中风有待检验的新的中心假设是,CD 8 + T细胞的脑浸润促进了 通过LIF/LIFR/ETGF介导的神经保护作用, 神经炎症和神经修复机制。提出了三个具体目标。目标1。建立 脑卒中后过继转移CD 8 + T细胞作为急性缺血性脑损伤的临床相关治疗 梗塞目标2.检验中风后过继转移CD 8+调节性T细胞促进长期免疫的假设 缺血性卒中后的神经恢复和神经修复。目标3.测试的假设 LIF/LIFR介导的ETGF释放对于CD 8 + Treg提供的神经保护作用是必需的, 神经修复这项研究将是第一个严格研究CD 8 + T细胞在缺血性脑损伤中的作用的研究。 损伤这些结果将有助于我们对中风免疫调节的理解,并阐明CD 8 + Treg 转移作为一种潜在的治疗策略。

项目成果

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Jun Chen其他文献

Corrosion wear characteristics of TC4, 316 stainless steel, and Monel K500 in artificial seawater
TC4、316不锈钢、蒙乃尔K500在人工海水中的腐蚀磨损特性
  • DOI:
    10.1039/c7ra03065g
  • 发表时间:
    2017-04
  • 期刊:
  • 影响因子:
    3.9
  • 作者:
    Jun Chen
  • 通讯作者:
    Jun Chen

Jun Chen的其他文献

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{{ truncateString('Jun Chen', 18)}}的其他基金

BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
  • 批准号:
    10696455
  • 财政年份:
    2023
  • 资助金额:
    $ 40.75万
  • 项目类别:
Adiponectin on cerebrovascular regulation in vascular cognitive impairment and dementia (VCID)
脂联素对血管性认知障碍和痴呆 (VCID) 的脑血管调节作用
  • 批准号:
    10542359
  • 财政年份:
    2022
  • 资助金额:
    $ 40.75万
  • 项目类别:
Activation of the RXR/PPARγ axis improves long-term outcomes after ischemic stroke in aged mice
RXR/PPARγ 轴的激活可改善老年小鼠缺血性中风后的长期结果
  • 批准号:
    10364171
  • 财政年份:
    2022
  • 资助金额:
    $ 40.75万
  • 项目类别:
Activation of the RXR/PPARγ axis improves long-term outcomes after ischemic stroke in aged mice
RXR/PPARγ 轴的激活可改善老年小鼠缺血性中风后的长期结果
  • 批准号:
    10609791
  • 财政年份:
    2022
  • 资助金额:
    $ 40.75万
  • 项目类别:
Methods for microbiome compositional data
微生物组组成数据的方法
  • 批准号:
    10338342
  • 财政年份:
    2022
  • 资助金额:
    $ 40.75万
  • 项目类别:
Methods for microbiome compositional data
微生物组组成数据的方法
  • 批准号:
    10580718
  • 财政年份:
    2022
  • 资助金额:
    $ 40.75万
  • 项目类别:
Methods for Analysis of Genomic Data with Auxiliary Information
具有辅助信息的基因组数据分析方法
  • 批准号:
    10188885
  • 财政年份:
    2021
  • 资助金额:
    $ 40.75万
  • 项目类别:
Methods for Analysis of Genomic Data with Auxiliary Information
具有辅助信息的基因组数据分析方法
  • 批准号:
    10415152
  • 财政年份:
    2021
  • 资助金额:
    $ 40.75万
  • 项目类别:
Inflammation resolution, neuroprotection, and brain repair to promote stroke recovery
炎症消解、神经保护和大脑修复以促进中风康复
  • 批准号:
    10261320
  • 财政年份:
    2017
  • 资助金额:
    $ 40.75万
  • 项目类别:
Inflammation resolution, neuroprotection, and brain repair to promote stroke recovery
炎症消解、神经保护和大脑修复以促进中风康复
  • 批准号:
    9697886
  • 财政年份:
    2017
  • 资助金额:
    $ 40.75万
  • 项目类别:
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