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

• 批准号: 9268088
• 负责人: Fudong Liu
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 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/9268088
• 关键词: Acute; Affect; Animals; Area; Behavioral; Binding; Biological; Birth; Blood; Brain; CCL2 gene; CX3CL1 gene; Cause of Death; Cells; Child; Clinical; Clinical Trials; Cognitive deficits; Development; Disease; Environment; Female; Flow Cytometry; Fractalkine; Functional disorder; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Gene Proteins; Genetic; Glial Fibrillary Acidic Protein; Goals; Gonadal Steroid Hormones; Hippocampus (Brain); Hormonal; Hour; ITGAM gene; Immune; Immune response; Immunohistochemistry; Impairment; Individual; Infant; Infiltration; Inflammatory; Inflammatory Response; Injectable; Injury; Innate Immune Response; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Knock-in; Knock-out; Laboratories; Lead; Learning; Leukocytes; Mediating; Membrane; Microglia; Modeling; Morphology; Mus; Neonatal; Neurons; Neuroprotective Agents; Outcome; PTPRC gene; Pathway interactions; Perinatal anoxic ischemic brain injury; Peripheral; Pharmacology; Recombinants; Rice; Rodent; Role; Secondary to; Serum; Sex Characteristics; Signal Pathway; Signal Transduction; Spleen; Testing; Testosterone; Therapeutic; Therapeutic Intervention; Western Blotting; age related; arginase; base; chemokine; chemokine receptor; cohort; cytokine; disability; experimental study; 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; perinatal outcomes; postnatal; public health relevance; pup; receptor; red fluorescent protein; response; sex; sexual dimorphism; targeted treatment; therapeutic target

 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.

 描述（由适用提供）：围产期缺氧 - 缺血性脑病（HIE）是新生儿死亡和长期残疾的主要原因。迄今为止，尽管临床试验表明体温过低在改善HIE婴儿的预后方面的好处，但尚无单独的神经保护剂被证明是安全有效的。迫切需要针对这种毁灭性疾病进行优化的新疗法。临床上，男性对新生儿Hie更敏感。但是，性别差异的基础机制尚不清楚。先天免疫应答在HIE的病理生理中具有基本作用。小胶质细胞激活是免疫响应的关键引发剂，并由内源性抑制信号（主要CX3CL1/CX3CR1信号通路）调节。最近的研究发现，在正常情况下，在新生儿大脑中的小胶质细胞数量，激活和表达的膜受体中存在性二态性。然而，这些基本的性别差异如何影响对新生儿损伤（例如HIE）的反应。我们假设在男性和女性新生儿中，小胶质细胞在HIE后被不同地激活，从而导致免疫复杂和缺血性结局差异。稻米瓦努奇模型将用于在两性男女的第10天（P10）小鼠中诱导HIE。在AIM 1中，我们将检验以下假设：由于CX3CL1/CX3CR1信号传导的性二态性，小胶质激活和HIE结果中存在性别差异。 CX3CL1/CX3CR1信号通路的药理增强和遗传缺失将进行机械研究该途径对HIE的操纵的影响。在AIM 2中，我们将使用“圣诞节”鼠标（CX3CR1GFP/+CCR2RFP/+）来研究中央和周围免疫的性二态性。 “圣诞节”小鼠模型使我们能够将血液来源的巨噬细胞与居民小胶质细胞区分开。通过将“圣诞节”小鼠与流式细胞仪和IHC一起使用，我们将能够研究中央和周围免疫响应的性别差异，并研究每个成分（中央与外围）在HIE中的作用。这些探索性研究将使人们更好地了解HIE的性别机制，并有助于我们识别和优化儿童治疗干预的生物学靶标。