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Sex Differences in Immune Responses to Hypoxic-Ischemic Encephalopathy

缺氧缺血性脑病免疫反应的性别差异

基本信息

批准号：
9033420
负责人：
Fudong Liu
金额：
$ 23.1万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9033420
关键词：
Acute Affect Animals Area Behavioral Binding Biological Birth Blood Brain CCL2 gene CX3CL1 gene Cause of Death Cells Child Clinical Trials Cognitive deficits Disease Environment Female Flow Cytometry Fractalkine Functional disorder G-Protein-Coupled Receptors Genes Genetic Enhancement Glial Fibrillary Acidic Protein Goals Gonadal Steroid Hormones Hippocampus (Brain)Hormonal Hour ITGAM gene Immune Immune response Immunohistochemistry Immunologic Memory Individual Infant Infiltration Inflammatory Inflammatory Response Injury Ischemia Ischemic Brain Injury Ischemic Stroke Knock-in Knock-out Laboratories Lead Learning Leukocytes Mediating Membrane Microglia Modeling Mus Neonatal Neurons Neuroprotective Agents Outcome PTPRC gene Pathway interactions Perinatal anoxic ischemic brain injury Peripheral Recombinants Rice Rodent Role Secondary to Serum Sex Characteristics Sexual Development Signal Pathway Signal Transduction Spleen Testing Testosterone Therapeutic Therapeutic Intervention Western Blotting age related arginase base chemokine chemokine receptor cohort cytokine disability improved outcome ischemic lesion macrophage male monocyte mouse model natural hypothermia neonatal brain neonatal death neonatal hypoxic-ischemic brain injury neonatal injury neonate neuroinflammation novel therapeutics postnatal public health relevance pup receptor red fluorescent protein research study response sex sexual dimorphism targeted treatment therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Perinatal hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal death and long-term disability. To date, no individual neuroprotective agent has been proven safe and effective, although clinical trials have shown benefits of hypothermia in improving outcomes in HIE infants. Novel therapies optimized for this devastating disease are urgently needed. Clinically, males are more sensitive to neonatal HIE; however, the mechanisms underlying the sex difference are unknown. The innate immune response has a fundamental role in the pathophysiology of HIE. Microglial activation is the key initiator of the immune response, and is regulated by the endogenous inhibitory signals, primarily CX3CL1/CX3CR1 signaling pathway. Recent studies have found that sexual dimorphism exists in microglia number, activation, and expressed membrane receptors in the neonatal brain under normal conditions. Nevertheless, how these basal sex differences affect the response to a neonatal injury such as HIE remains largely unexplored. We hypothesize that microglia are differentially activated after HIE in male and female neonates, leading to differential immune responses and ischemic outcomes. The Rice-Vannucci model will be used to induce HIE in post-natal day 10 (P10) mice of both sexes. In Aim 1, we will test the hypothesis that sex differences exist in microglial activation and in HIE outcomes due to the sexual dimorphism in CX3CL1/CX3CR1 signaling. Pharmacological enhancement and genetic deletion of CX3CL1/CX3CR1 signaling pathway will be performed to mechanistically study the effect of manipulation of this pathway on HIE. In Aim 2, we will use "Christmas" mouse (CX3CR1gfp/+CCR2rfp/+) to investigate the sexual dimorphism in central and peripheral immune response to HIE. The "Christmas" mouse model allows us to differentiate blood-derived macrophages from resident microglia. By using "Christmas" mice together with flow cytometry and IHC, we will be able to study the sex difference in both the central and peripheral immune response, and investigate the role of each component (central vs. peripheral) in HIE. These exploratory studies will lead to better understanding of sex-specific mechanisms underlying HIE and will help us identify and optimize biological targets for therapeutic intervention in children.