Alarmin-mediated control of CNS infection

警报素介导的中枢神经系统感染控制

• 批准号: 10120929
• 负责人: TAJIE H. HARRIS
• 金额: $ 31.62万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10120929
• 关键词: APP-PS1; Administrative Supplement; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Amyloid; Amyloid deposition; Astrocytes; Award; Binding; Biology; Blood - brain barrier anatomy; Brain; Brain Pathology; Cell Adhesion Molecules; Cell Death; Cells; Central Nervous System Infections; Data; Defect; Disease Progression; Endothelial Cells; Endothelium; Excision; Family; Family member; Funding; Gene Proteins; Genes; Genetic study; Human; Human Genetics; Immune; Immune response; Immune system; Immunity; Infection; Inflammation; Inflammatory; Injections; Innate Immune Response; Interleukin-1; Knockout Mice; Laboratories; Mediating; Microglia; Monitor; Mouse Strains; Mus; Mutation; Parents; Pathway interactions; Peripheral; Phagocytes; Phagocytosis; Population; Production; Role; Senile Plaques; Signal Transduction; Single Nucleotide Polymorphism; Study models; Testing; Therapeutic; aged; base; brain endothelial cell; cell injury; cell type; chemokine; cytokine; genome wide association study; interleukin-1 receptor accessory protein; macrophage; monocyte; mouse model; neuroinflammation; neuron loss; overexpression; receptor; recruit; response; response to injury; tool; transcriptome sequencing

PROJECT SUMMARY The funded award (R01NS112516) focuses on the role of alarmins in activating innate immune responses in the brain. My laboratory has studied the role of two alarmins, IL-1a and IL-33, that independently trigger inflammation and protective immunity against a brain infection. Interestingly, IL-1a and IL-33, share a co- receptor, interleukin-1 receptor accessory protein (IL-1RAP). Of relevance to Alzheimer’s Disease (AD) and the basis of this administrative supplement application, SNPs in il1rap have been associated with AD progression, the accumulation of amyloid plaques, and decreased inflammation in the brain. These findings also implicate the role for alarmins that bind and signal through IL-1RAP (IL-1, IL-33, and the lesser studied IL-36 family members), molecules expressed in healthy cells that are released upon cell death and initiate local inflammation. Of note, genome-wide association studies have also implicated SNPs in il1a and il33 in AD, but to a lesser degree. Taken together, several human genetic studies have implicated aberrant alarmin sensing in the progression of AD. My laboratory has been studying the expression, sensing, and importance of alarmins in the brain for several years. We have an extensive understanding of how these molecules promote immunity to infection and have unique tools to understand alarmin biology in AD. Importantly, we find that alarmins activate the brain to promote the entry of peripheral immune cells to the CNS during infection, especially phagocytic monocyte-derived macrophages. We hypothesize that alarmin signaling is necessary to facilitate enhanced phagocytosis in the AD brain. To test this hypothesis, we propose three aims that mirror those of the funded application.

项目摘要 该基金（R 01 NS 112516）的重点是alarmins在激活先天免疫反应中的作用， 大脑我的实验室已经研究了两种alarmins的作用，IL-1a和IL-33，它们独立地触发 炎症和对脑部感染的保护性免疫。有趣的是，IL-1a和IL-33，共享一个共同的， 受体，白细胞介素-1受体辅助蛋白（IL-1 RAP）。与阿尔茨海默病（AD）相关， 基于该管理补充申请，il 1 rap中的SNP与AD进展相关， 淀粉样斑块的积累，以及大脑中炎症的减少。这些发现还表明， 结合并通过IL-1 RAP（IL-1、IL-33和较少研究IL-36家族）传递信号的警报素的作用 成员），在健康细胞中表达的分子，其在细胞死亡时释放并启动局部 炎症值得注意的是，全基因组关联研究也涉及AD中il 1a和il 33的SNP，但 在较小的程度上。总之，几项人类遗传学研究已经暗示了异常的警报素传感， AD的进展。我的实验室一直在研究警报素的表达、感知和重要性 在大脑里呆了好几年。我们对这些分子如何促进免疫力有着广泛的了解 并拥有独特的工具来了解AD中的警报生物学。重要的是，我们发现， 在感染期间激活大脑以促进外周免疫细胞进入CNS，特别是 吞噬单核细胞衍生的巨噬细胞。我们假设alarmin信号是促进 增强了AD脑中的吞噬作用。为了验证这一假设，我们提出了三个目标，反映了那些 资助申请。