Microglia mediate cognitive dysfunction in elderly survivors of pneumonia

小胶质细胞介导老年肺炎幸存者的认知功能障碍

基本信息

批准号：
10354214
负责人：
GR Scott Budinger
金额：
$ 44万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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：
2022-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10354214
关键词：
2019-nCoV Ablation Acute Adrenergic alpha-Antagonists Age-associated memory impairment Aging Alzheimer&apos s Disease Animal Model Animals Apoptotic Autopsy Behavioral Biological Models Brain COVID-19 pneumonia COVID-19 survivors Cardiovascular system Cells Chronic Kidney Failure Clinical Cognition Cognitive Cognitive deficits Cues Data Dementia Development Down-Regulation Elderly Embryonic Development Event Functional disorder Genes Genetic Hippocampus (Brain)Homeostasis Hospitals Human Immunologist Impaired cognition Infection Inflammatory Influenza A virus Intuition Laboratories Link Long-Term Potentiation Longevity Macrophage Colony-Stimulating Factor Macrophage Colony-Stimulating Factor Receptor Maintenance Measures Mediating Methods Microglia Microscopy Modeling Mus Nerve Degeneration Neuronal Plasticity Neurons Pathology Patients Performance Phagocytes Pharmacology Play Pneumonia Population Predisposition Public Health Recovery Reporting Resources Respiration Disorders Risk Role Signal Transduction Skeletal Muscle Survivors Synapses Techniques Testing Tissues United States Validation Virus age related axon guidance behavior measurement brain tissue clinically relevant cognitive function cognitive recovery cognitive testing cytokine data repository frontal lobe functional disability high reward high risk influenza A pneumonia macrophage mortality mouse model pathogen protein aggregation self-renewal senescence severe COVID-19 single-cell RNA sequencing transcriptome sequencing transcriptomics young adult

项目摘要

PROJECT SUMMARY Multiple lines of clinical evidence demonstrate a link between pneumonia, cognitive impairment, and dementia in the elderly. The mechanisms underlying this susceptibility, however, remain unclear. Clinical and experimental evidence suggests that microglia – resident macrophages in the brain – play a key role in both maintaining normal brain homeostasis and upon activation can drive neurodegeneration and cognitive decline. The role of microglia in cognitive decline in elderly survivors of pneumonia is unknown. In this R21, we propose to test two high-risk, high-reward hypotheses: First, we hypothesize that cell-autonomous changes in microglia with aging necessary for the persistent cognitive decline after pneumonia in old animals. Second, we hypothesize that transcriptomic changes in the microglia and brain observed in mice after pneumonia will mirror those observed in patients with pneumonia. We propose to test these hypotheses with two Specific Aims. Aim 1. To determine whether cell-autonomous, age-related dysfunction in microglia precludes cognitive recovery in old mice following influenza A virus-induced pneumonia. We will use pharmacological approaches to deplete microglia in young and old mice during recovery from influenza A infection and measure performance on cognitive tests, and transcriptomic changes in microglia and the brain using RNA-Seq with validation using spatial transcriptomics. Aim 2. To compare microglial activation in patients who succumb to SARS-CoV-2 pneumonia with other pneumonia and non-pneumonia controls. We will collect hippocampal tissue during a rapid autopsy in patients who die after SARS-CoV-2 pneumonia and analyze it using single-cell RNA-seq and spatial transcriptomics.

项目摘要多种临床证据表明肺炎，认知障碍和痴呆之间有联系在过去。但是，这种敏感性的基础机制尚不清楚。临床和实验有证据表明，小胶质细胞 - 居民大脑中的巨噬细胞 - 在维持正常的大脑体内平衡和激活后会促进神经退行性和认知能力下降。的作用小胶质细胞在肺炎生存的旧生存中的认知能力下降中尚不清楚。在此R21中，我们建议测试两个高风险，高回报的假设：首先，我们假设小胶质细胞自主变化与老动物肺炎后持续认知能力下降所必需的衰老。第二，我们假设肺炎后小鼠观察到的小胶质细胞和大脑的转录组变化会反映那些在肺炎患者中观察到的。我们建议用两个特定的特定假设检验这些假设目标。目的1。确定小胶质细胞中的细胞自主性，与年龄相关的功能障碍是否排除在影响Za病毒引起的肺炎后，旧小鼠的认知恢复。我们将使用从影响力恢复期间，年轻小鼠和老鼠小鼠的小胶质细胞的药理方法认知测试的感染和测量表现，小胶质细胞和大脑的转录组变化使用使用空间转录组学验证的RNA-Seq。目标2。比较小胶质细胞激活屈服于其他肺炎和非肺炎对照的患者。在SARS-COV-2肺炎后死亡的患者和使用单细胞RNA-seq和空间转录组学分析它。