Activating proteostasis in aging resident macrophages to prevent muscle and cognitive dysfunction after pneumonia

激活老化常驻巨噬细胞中的蛋白质稳态，以预防肺炎后的肌肉和认知功能障碍

• 批准号: 10197744
• 负责人: Alexander Misharin
• 金额: $ 39.93万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10197744
• 关键词: Aging; Animals; Apoptotic; Award; Bacterial Pneumonia; Brain; Cell Proliferation; Chronic; Cognitive; Complex; Data; Dementia; Disease; Distant; Elderly; Endocrine; Exhibits; Flow Cytometry; Functional disorder; Funding Opportunities; Gene Expression; Genes; Genetic; Healthcare; Impaired cognition; Impairment; Individual; Infection; Influenza A virus; Instruction; Interleukin-6; Kidney; Learning; Link; Literature; Lung; Memory; Microglia; Mitochondria; Modernization; Molecular; Molecular Chaperones; Morbidity - disease rate; Motor; Mus; Muscle; Muscle function; Muscle satellite cell; Muscular Atrophy; Myocardial; Neurocognitive Deficit; Organ; Pathway interactions; Patients; Phagocytosis; Pharmacology; Phenocopy; Physiological; Pneumonia; Process; Proliferating; Recovery; Research; Risk; Signal Pathway; Signal Transduction; Skeletal Muscle; Survivors; Testing; Tissues; Up-Regulation; Viral Pneumonia; Viremia; activating transcription factor 4; age related; aged; behavior test; biological adaptation to stress; cognitive function; cognitive recovery; end of life; healthspan; improved; influenza A pneumonia; injury and repair; juvenile animal; lung injury; macrophage; mitochondrial metabolism; molecular marker; mouse model; prevent; proteostasis; receptor function; repaired; response; satellite cell; scavenger receptor; skeletal muscle wasting; targeted treatment; transcriptome; transcriptomics; ubiquitin-protein ligase

PROJECT SUMMARY Elderly pneumonia survivors are at increased risk of developing skeletal muscle atrophy that impairs mobility, dementia, and cognitive dysfunction, which are perhaps the most debilitating limitations to health-span in the elderly. We found critical features of this multiple organ dysfunction after pneumonia are recapitulated in mice, allowing us to use mouse models to elucidate mechanisms that can be targeted for therapy. In the first cycle of this award, we found that a systemic increase in IL-6 during influenza A-induced pneumonia was necessary for upregulation of the E3-ubiquitin ligase atrogin-1 and muscle wasting in both young and aged animals. While muscle function was rapidly restored in young animals, we never observed it to recover in older animals even months after pneumonia. We observed that muscle satellite cells necessary for muscle repair failed to proliferate after pneumonia in aged, but not in young animals, which was associated with decreased expression of the scavenger receptor Mertk. Genetic disruption of genes required for phagocytosis (Mertk, C3, Cx3cr1) in young animals phenocopied the impaired satellite cell proliferation after influenza A pneumonia in aged animals. In parallel studies in the brain, we found that while young mice recover cognitive function after influenza A infection, older animals develop persistent neurocognitive impairment. Highly sensitive transcriptomic profiling of flow sorted microglia showed aged microglia exhibited decreased expression of scavenger receptors, including Mertk. This was associated with reduced expression of genes related to axonogenesis, learning and memory in whole brain transcriptomes from aged compared with young animals after influenza A-induced pneumonia. Tissue resident muscle macrophages and microglia from young mice robustly activated the integrated stress response (ISR) after influenza A infection as evidenced by increased expression of Activating Transcription Factor-4 (Atf4) and molecular chaperones, but aged mice lacked this response. These preliminary data support our hypothesis that age-related loss of scavenger receptor function impairs phagocytosis in tissue resident macrophages necessary for the molecular and physiologic recovery of skeletal muscle and cognitive function after pneumonia. We will determine whether these age-related changes can be reversed by inhibition of mitochondrial complex I via the ISR and/or ATF4 in two interrelated specific aims: Aim1. To determine whether scavenger receptor activity in resident skeletal muscle macrophages and microglia and is necessary for the recovery of cognitive and skeletal muscle function after influenza A- induced pneumonia. Aim 2. To determine whether modulation of mitochondrial metabolism, the integrated stress response and/or ATF4 can restore scavenger function of the microglia and skeletal muscle macrophages to improve cognitive and motor function in aged mice after pneumonia.

项目摘要 老年肺炎幸存者的风险增加了损害流动性的骨骼肌萎缩， 痴呆症和认知功能障碍，这可能是对健康中最令人衰弱的局限性 老年。我们发现，在小鼠中概括了这种多个器官功能障碍的关键特征， 允许我们使用小鼠模型来阐明可以针对治疗的机制。在第一个周期 该奖项，我们发现在流感A引起的肺炎中IL-6的系统性增加是必要的 E3-泛素连接酶Atrogin-1和年轻动物中的肌肉浪费的上调。尽管 在年轻动物中，肌肉功能迅速恢复，我们从未观察到它在老年动物中恢复 肺炎几个月后。我们观察到肌肉修复所需的肌肉卫星细胞无法增殖 年龄肺炎后，但在年轻动物中却没有 清道夫受体Mertk。年轻的吞噬作用（MERTK，C3，CX3CR1）所需的基因的遗传破坏 动物在年龄动物的肺炎流感肺炎后，卫星细胞增殖受损。在 在大脑中的平行研究中，我们发现，虽然年轻小鼠在感染流感后恢复了认知功能，但 老年动物会出现持续的神经认知障碍。流量的高度敏感转录组学分析 分类的小胶质细胞显示老化的小胶质细胞表现出降低的清道夫受体表达，包括MERTK。 这与整个与轴突发生，学习和记忆有关的基因表达降低有关 与流感A诱导的肺炎相比，老年人的脑转录组与年轻动物相比。组织 年轻小鼠的常驻肌肉巨噬细胞和小胶质细胞牢固地激活了综合应力反应 （ISR）在流感A感染后，激活转录因子-4的表达增加（ATF4）证明了这一点（ATF4） 和分子伴侣，但老年小鼠缺乏这种反应。 这些初步数据支持我们的假设，即与年龄相关的清道夫受体功能损害损害 骨骼分子和生理恢复所需的组织驻留巨噬细胞中的吞噬作用 肺炎后的肌肉和认知功能。我们将确定这些与年龄相关的变化是否可以 通过抑制线粒体复合物I通过ISR和/或ATF4的抑制作用，以两个相互关联的特定目的相反： AIM1。确定居民骨骼肌巨噬细胞中的清道夫受体活性和 小胶质细胞是流感a-之后认知和骨骼肌功能所必需的 诱发肺炎。 目的2。确定线粒体代谢的调节，综合应力反应 和/或ATF4可以恢复小胶质细胞和骨骼肌巨噬细胞的清道夫功能 改善肺炎后老年小鼠的认知和运动功能。