Neutrophils and Monocytes in Pediatric Ischemic Stroke
小儿缺血性中风中的中性粒细胞和单核细胞
基本信息
- 批准号:10629365
- 负责人:
- 金额:$ 43.09万
- 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:2022-06-01 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:1 year oldAcuteAdaptive Immune SystemAddressAdultAffectBirthBlood - brain barrier anatomyCaringCellsCerebrovascular systemChildhoodChildhood strokeClinical ManagementCognitive deficitsCrimeDataDevelopmentDichloromethylene DiphosphonateFamilyFlow CytometryGelatinase BGene ExpressionGoalsHeterogeneityImmuneImmune System DiseasesImmune TargetingImmune responseImmunotherapyIncidenceInfantInfarctionInfectionInfiltrationInflammationInflammatoryInflammatory ResponseInjectionsInterleukin-1InvadedIschemic StrokeLeptomeningesLipopolysaccharidesLiposomesLyticMMP9 geneMeasuresMeningesMessenger RNAMusNeurogliaNeurologicNeutrophil InfiltrationOralOutcomePathogenicityPathologicPediatric Brain InjuryPlayReverse Transcriptase Polymerase Chain ReactionRisk FactorsRoleStrokeTestingVirulenceWaterbrain parenchymacisterna magnacohortcytokinedesigneffective therapyfunctional improvementimmunomodulatory therapiesinhibitorinsightmonocytemotor deficitmouse modelneonateneutrophilnovelpost strokepostnatalpreservationpreventpublic health relevancesingle-cell RNA sequencingtissue repairtranscriptometranscriptome sequencing
项目摘要
PROJECT SUMMARY (Description)
Ischemic stroke affects around 1 in 1600 to 4000 births, has the highest incidence in neonates and infants (<
one year of age), and may cause neurological sequalae, including motor and cognitive deficits. Infection and
immune responses are a major risk factor for pediatric stroke, but no immune-directed therapies are available.
In fact, supportive measures remain the mainstay of pediatric stroke care, since the lytic treatment carries a
high in neonates with fragile cerebrovascular vessels. In this project, we will use a murine model of pediatric
stroke, with and without lipopolysaccharides (LPS)-sensitization, to test the pathological roles of neutrophils
and monocytes towards the development of immunomodulation therapies.
Aim 1: To clarify how immune cells breach the pial/glia limitans barrier in pediatric LPS/stroke. We will use flow
cytometry and single-cell RNA-Seq analysis to determine the compositions and transcriptome of immune cells
in the meninges after LPS/stroke, and test whether anti-MMP9 treatment prevents the neutrophil influx.
Aim 2: To test whether there are two waves of monocytic infiltrates with distinct functions in pediatric stroke. We
will use CCR2-CreER mice to track monocytic infiltrates and single-cell RNA-Seq analysis, as well as, block the
influx of monocytes at different stage after stroke to address this issue.
Aim 3: To determine what constitutes the meninges-incurred pathogenicity of neutrophils after pediatric
LPS/stroke. Our RNA-Seq results suggest that neutrophils acquire IL-36gamma, a novel family of the IL-1
family cytokine, in the meninges. We will validate these findings and test the benefits of anti-IL36R treatment.
Successful completion of this project will shed insights into the mechanisms of pediatric ischemic stroke and
whether neutrophil/monocyte-targeted immunomodulation therapies could provide better clinical management.
项目概要(说明)
缺血性卒中影响约1/1600至4000的新生儿,在新生儿和婴儿中发病率最高(<
一岁),并可能导致神经后遗症,包括运动和认知缺陷。感染和
免疫反应是儿童中风的主要危险因素,但没有免疫导向疗法可用。
事实上,支持性措施仍然是儿科卒中护理的主要内容,因为溶解性治疗具有
新生儿脆弱的脑血管高。在这个项目中,我们将使用一个小鼠模型,
中风,有和没有脂多糖(LPS)致敏,以测试中性粒细胞的病理作用
和单核细胞的免疫调节疗法的发展。
目的1:阐明儿童LPS/卒中中免疫细胞如何突破软脑膜/胶质界膜屏障。我们将使用Flow
流式细胞术和单细胞RNA-Seq分析,以确定免疫细胞的组成和转录组
在LPS/中风后的脑膜中,并测试抗MMP 9治疗是否阻止中性粒细胞流入。
目的2:探讨小儿脑卒中是否存在功能不同的两波单核细胞浸润。我们
将使用CCR 2-CreER小鼠来跟踪单核细胞浸润和单细胞RNA-Seq分析,以及,阻断
中风后不同阶段单核细胞的涌入可以解决这个问题。
目的3:确定小儿脑膜炎后中性粒细胞的致病性
LPS/卒中。我们的RNA-Seq结果表明,中性粒细胞获得IL-36 γ,一个新的IL-1家族,
家族细胞因子,在脑膜中。我们将验证这些发现并测试抗IL 36 R治疗的益处。
该项目的成功完成将有助于深入了解儿童缺血性卒中的机制,
中性粒细胞/单核细胞靶向免疫调节疗法是否可以提供更好的临床管理。
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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Chia-Yi Kuan其他文献
Chia-Yi Kuan的其他文献
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{{ truncateString('Chia-Yi Kuan', 18)}}的其他基金
Monocyte-Derived Microglia in Development and after Neonatal Brain Injury
发育中和新生儿脑损伤后的单核细胞衍生的小胶质细胞
- 批准号:
10593385 - 财政年份:2023
- 资助金额:
$ 43.09万 - 项目类别:
Treating neurotoxicity and cognitive deficits due to hyperphosphorylated tau.
治疗由过度磷酸化 tau 引起的神经毒性和认知缺陷。
- 批准号:
10815399 - 财政年份:2023
- 资助金额:
$ 43.09万 - 项目类别:
Perivascular Fibroblast-Endothelium Interactions in Hypertension and Cerebral Ischemia
高血压和脑缺血中血管周围成纤维细胞-内皮细胞的相互作用
- 批准号:
10463370 - 财政年份:2022
- 资助金额:
$ 43.09万 - 项目类别:
Perivascular Fibroblast-Endothelium Interactions in Hypertension and Cerebral Ischemia
高血压和脑缺血中血管周围成纤维细胞-内皮细胞的相互作用
- 批准号:
10598600 - 财政年份:2022
- 资助金额:
$ 43.09万 - 项目类别:
Neutrophils and Monocytes in Pediatric Ischemic Stroke
小儿缺血性中风中的中性粒细胞和单核细胞
- 批准号:
10529933 - 财政年份:2022
- 资助金额:
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Creatine Transporter Deficiency and Brain Energetics
肌酸转运蛋白缺乏和脑能量学
- 批准号:
10442483 - 财政年份:2018
- 资助金额:
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Creatine Transporter Deficiency and Brain Energetics
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- 批准号:
10217271 - 财政年份:2018
- 资助金额:
$ 43.09万 - 项目类别:
Microglia- Monocyte Interactions following Perinatal Brain Injury
围产期脑损伤后小胶质细胞-单核细胞相互作用
- 批准号:
9198866 - 财政年份:2016
- 资助金额:
$ 43.09万 - 项目类别:
Microglia- Monocyte Interactions following Perinatal Brain Injury
围产期脑损伤后小胶质细胞-单核细胞相互作用
- 批准号:
9110552 - 财政年份:2016
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- 批准号:
8905538 - 财政年份:2015
- 资助金额:
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