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.

项目概要（描述）缺血性中风影响大约每 1600 至 4000 名新生儿中就有 1 人患有缺血性中风，新生儿和婴儿的发病率最高（< 一岁），并可能导致神经系统后遗症，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，但目前尚无免疫导向疗法。事实上，支持性措施仍然是儿科中风护理的支柱，因为溶解治疗具有一定的效果。脑血管脆弱的新生儿发病率较高。在这个项目中，我们将使用儿科小鼠模型中风，有或没有脂多糖 (LPS) 致敏，以测试中性粒细胞的病理作用和单核细胞以开发免疫调节疗法。目标 1：阐明儿科 LPS/中风中免疫细胞如何突破软脑膜/神经胶质细胞屏障。我们将使用流细胞计数和单细胞 RNA-Seq 分析以确定免疫细胞的组成和转录组 LPS/中风后的脑膜中，并测试抗 MMP9 治疗是否可以阻止中性粒细胞流入。目标 2：测试小儿卒中中是否存在具有不同功能的两波单核细胞浸润。我们将使用 CCR2-CreER 小鼠追踪单核细胞浸润和单细胞 RNA-Seq 分析，以及阻断在中风后的不同阶段单核细胞的涌入可以解决这个问题。目标 3：确定小儿脑膜炎后中性粒细胞致病性的构成因素 LPS/行程。我们的 RNA 测序结果表明中性粒细胞获得 IL-36gamma，这是 IL-1 的一个新家族家族细胞因子，位于脑膜中。我们将验证这些发现并测试抗 IL36R 治疗的益处。该项目的成功完成将深入了解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。