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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：
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/10629365
关键词：
1 year old Acute Adaptive Immune System Address Adult Affect Birth 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 Oral Outcome Pathogenicity Pathologic Pediatric Brain Injury Play Reverse Transcriptase Polymerase Chain Reaction Risk Factors Role Stroke Testing Virulence Water brain parenchyma cisterna magna cohort cytokine design effective therapy functional improvement immunomodulatory therapies 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.

项目概述（描述）