Role of T cells in ischemic brain damage
T细胞在缺血性脑损伤中的作用
基本信息
- 批准号:9884832
- 负责人:
- 金额:$ 32.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-04-01 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAcute Brain InjuriesAffectAlteplaseAnimal ModelAntibodiesBlocking AntibodiesBrainBrain InjuriesCause of DeathCell physiologyCellsCerebral IschemiaChronicClinical ResearchDataDevelopmentFc ReceptorFlow CytometryGenetically Engineered MouseGoalsHelper-Inducer T-LymphocyteHeterogeneityHumanHypoxiaImmune responseImmune systemImmunohistochemistryIn SituIn VitroInfiltrationInflammationInflammatoryInjuryIschemic Brain InjuryIschemic StrokeLeadManipulative TherapiesMapsMediator of activation proteinMiddle Cerebral Artery OcclusionMusNervous System TraumaNeuraxisNeuronal DysfunctionNeuronsPathogenesisPathogenicityPathologicPathway interactionsPhaseProductionReceptor SignalingRegulatory PathwayReporterRoleSignal TransductionStrokeT-LymphocyteTNF geneTestingTissuesTransgenic MiceTumor-infiltrating immune cellsUnited StatesWorkacute strokebrain tissuecell motilitycytokinedisabilityin vivoinflammatory milieuinterleukin-21interleukin-21 receptorischemic injuryneuroinflammationneuron lossnew therapeutic targetnovelpost strokepreclinical studyreceptorreceptor expressionrecruitspatiotemporalstroke modelstroke therapytargeted treatment
项目摘要
PROJECT SUMMARY/ABSTRACT
Stroke is one of the leading causes of death and disability worldwide and is the third leading cause of death
and disability in the United States. Clinical and preclinical studies suggest the importance of inflammation in
acute and chronic neuronal tissue damage following ischemic stroke; however, the mechanisms and cells
involved in neuroinflammation are not fully understood. There is currently no available treatment for targeting
the acute immune response that develops in the brain during cerebral ischemia, and no new treatment has
been introduced to stroke therapy since the discovery of tissue plasminogen activator therapy in 1996. We
discovered that interleukin 21 (IL21) is a major contributor to acute brain injury after ischemic stroke. IL21
expressing cells were detected in perivascular regions and the infarcted parenchyma of ischemic human brain
tissues. This raises the possibility that IL21–targeting therapies adjunct to current treatments might be
beneficial in stroke management. The long-term goal of this work is to understand how to manipulate the
acute inflammation following ischemic injury in order to inhibit stroke-induced tissue damage. The objective of
this proposal is to define the mechanisms by which pathogenic follicular helper T cells (Tfh) and IL21 are
involved in acute stroke-induced injury. The specific hypothesis is that the recently discovered circulating
pathogenic IL21-producing Tfh cells infiltrate into ischemic tissues in the brain, where IL21 contributes to tissue
damage by inducing neuronal death. Three aims will study how Tfh cells and IL21 contribute to ischemic injury
in the brain. In Aim 1, we will elucidate the pathways that drive IL21-producing Tfh cell infiltration, development
and function in the CNS during different stages of ischemic injury induced by transient Middle Cerebral Artery
Occlusion (tMCAO). We propose that selective Tfh cell recruitment blockers could decrease tissue damage in
stroke. In Aim 2, we will evaluate spatiotemporal expression of IL21R in the ischemic brain and test potential
regulator(s) of IL21R expression on neurons. We propose that inhibiting IL21R expression on neurons could
decrease tissue damage in stroke. In Aim 3, we will characterize the role of IL21R on neurons in the
pathogenesis of ischemic stroke. We will evaluate acute and chronic ischemic damage and the CNS
inflammatory milieu in mice that selectively lack IL21R in neurons.
Successful completion of this work will lead to a better understanding of the mechanism by which
pathogenic IL21-producing cells promote damage in ischemic injury and identify new therapeutic
targets in stroke.
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)
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Zsuzsanna Fabry其他文献
Zsuzsanna Fabry的其他文献
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{{ truncateString('Zsuzsanna Fabry', 18)}}的其他基金
Regulation of Neuroinflammation by Meningeal Lymphatics
脑膜淋巴管对神经炎症的调节
- 批准号:
10581900 - 财政年份:2022
- 资助金额:
$ 32.91万 - 项目类别:
Regulation of Neuroinflammation by Meningeal Lymphatics
脑膜淋巴管对神经炎症的调节
- 批准号:
10682552 - 财政年份:2022
- 资助金额:
$ 32.91万 - 项目类别:
Graduate Training in Cellular and Molecular Pathogenesis of Human Diseases
人类疾病的细胞和分子发病机制研究生培训
- 批准号:
10187600 - 财政年份:2020
- 资助金额:
$ 32.91万 - 项目类别:
Graduate Training in Cellular and Molecular Pathogenesis of Human Diseases
人类疾病的细胞和分子发病机制研究生培训
- 批准号:
10620761 - 财政年份:2020
- 资助金额:
$ 32.91万 - 项目类别:
Graduate Training in Cellular and Molecular Pathogenesis of Human Diseases
人类疾病的细胞和分子发病机制研究生培训
- 批准号:
10413879 - 财政年份:2020
- 资助金额:
$ 32.91万 - 项目类别:
Neuroinflammation-induced lymphangiogenesis in the CNS
中枢神经系统中神经炎症诱导的淋巴管生成
- 批准号:
9769903 - 财政年份:2018
- 资助金额:
$ 32.91万 - 项目类别:
Neuroinflammation-induced lymphangiogenesis in the CNS
中枢神经系统中神经炎症诱导的淋巴管生成
- 批准号:
10224352 - 财政年份:2018
- 资助金额:
$ 32.91万 - 项目类别:
Neuroinflammation-induced lymphangiogenesis in the CNS
中枢神经系统中神经炎症诱导的淋巴管生成
- 批准号:
10449330 - 财政年份:2018
- 资助金额:
$ 32.91万 - 项目类别:














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