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：
10529933
负责人：
Chia-Yi Kuan
金额：
$ 43.09万
依托单位：
UNIVERSITY OF VIRGINIA
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：
https://reporter.nih.gov/project-details/10529933
关键词：
1 year old Acute Adaptive Immune System Address Adult Affect Birth Blood Blood - brain barrier anatomy Caring Cells Cerebrovascular system Childhood Childhood stroke Clinical Management Cognitive deficits Crime Data Development Dichloromethylene Diphosphonate Family Flow Cytometry Gelatinase B Gene Expression Goals Heterogeneity Immune Immune System Diseases Immune Targeting Immune response Immunotherapy Incidence Infant Infarction Infection Infiltration Inflammation Inflammatory Inflammatory Response Injections Interleukin-1 Invaded Ischemic Stroke Leptomeninges Lipopolysaccharides Liposomes Lytic MMP9 gene Measures Meninges Messenger RNA Mus Neuroglia Neurologic Neutrophil Infiltration Neutrophilic Infiltrate Oral Outcome Pathogenicity Pathologic Pediatric Brain Injury Play Reverse Transcriptase Polymerase Chain Reaction Risk Factors Role Stroke Testing Virulence Water base brain parenchyma cisterna magna cohort cytokine design effective therapy functional outcomes immunomodulatory therapies improved inhibitor insight monocyte motor deficit mouse model neonate neutrophil novel post stroke postnatal preservation prevent public health relevance single-cell RNA sequencing tissue repair transcriptome transcriptome 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.

项目摘要（描述）缺血性中风影响约1600至4000个出生的1个，在新生儿和婴儿中发病率最高（< 一岁），并可能导致神经系统序列，包括运动和认知缺陷。感染和免疫反应是小儿中风的主要危险因素，但没有免疫指导的疗法可用。实际上，支持措施仍然是小儿卒中护理的中流，因为裂解治疗带有A 具有脆弱的脑血管血管的新生儿高。在这个项目中，我们将使用小儿鼠模型中风，有或没有脂多糖（LPS）敏化，以测试中性粒细胞的病理作用和单核细胞发展免疫调节疗法。目的1：阐明儿科LPS/中风中的免疫细胞如何破坏PIAL/GLIA限制性屏障。我们将使用流细胞仪和单细胞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MMP9治疗是否可以防止中性粒细胞流入。 AIM 2：测试是否有两波单核细胞浸润，在小儿中风中具有不同的功能。我们将使用CCR2-creer小鼠跟踪单核细胞浸润和单细胞RNA-seq分析，并阻止中风后不同阶段的单核细胞涌入以解决这个问题。目标3：确定小儿嗜中性粒细胞的脑膜的致病性构成什么 LPS/中风。我们的RNA-seq结果表明，中性粒细胞获得IL-36-Gamma，这是一个新的IL-1家族家庭细胞因子，脑膜中。我们将验证这些发现并测试抗IL36R治疗的好处。该项目的成功完成将洞悉小儿缺血性中风的机制和中性粒细胞/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。