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Impact of Aging and Influenza Infection on Muscle Health

衰老和流感感染对肌肉健康的影响

基本信息

批准号：
9764231
负责人：
Laura Haynes
金额：
$ 20.84万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9764231
关键词：
Activities of Daily Living Aging Area Atrophic Automobile Driving Caring Cause of Death Cells Cellular Infiltration Clinical Coupled Data Down-Regulation Elderly Fiber Future Gait Gastrocnemius Muscle Gene Expression Genes Goals Growth Guide prevention Health Histology Immune Immune response Immunohistochemistry Immunologics In Vitro Individual Infection Infiltration Inflammation Inflammatory Influenza Injections Life Link Lung Measures Mediator of activation protein Modeling Molecular Morbidity - disease rate Morphology Mus Muscle Muscle Fibers Muscle function Muscular Atrophy Myoblasts Myopathy Natural regeneration Ontology Pathogenesis Pathway interactions Performance Physically Handicapped Plant Roots Proteins Publishing Recombinant Cytokines Recombinants Risk Serum Skeletal Muscle Statistical Models Stimulus System Testing Therapeutic Therapeutic Intervention Up-Regulation Viral Virus Diseases Work age related aged base chemokine cytokine data modeling disability experimental study flu frailty functional decline improved in vivo inflammatory milieu insight mouse model muscle aging prevent resilience response skeletal muscle wasting transcriptome transcriptome sequencing transcriptomics translational impact

项目摘要

PROJECT SUMMARY Influenza (flu) infection is a leading cause of death in the elderly. Additionally, and importantly, it is a common yet under-recognized contributor to excess morbidity, disability and loss of independence in the elderly. We recently published evidence of the first known pathophysiological link between flu infection and declining mobility performance utilizing a murine model. Despite that active flu infection is localized to the lungs, there are clear functional decrements and molecular alterations in the muscle with upregulation of muscle inflammation and atrophy genes and downregulation of positive regulators of muscle growth. Importantly, the impact of flu infection on these molecular changes and overall functional declines is more pronounced and prolonged with aging. Our primary goal in this R21 proposal is to identify specific mechanisms linking pulmonary flu infection to declines in muscle health and functional ability. Since our data does not support direct viral infection of skeletal muscle, we believe systemic factors are at the root of flu-induced muscle atrophy. Thus, infections that generate a systemic response comparable to flu would hypothetically also contribute to muscle loss with aging. Thus, this proposal will delve into mechanisms behind not only flu-induced muscle atrophy, but the underlying mechanisms of other inflammation and/or infection-induced myopathy and disability with aging. To identify potential mechanisms behind flu-induced muscle atrophy, we will employ an unbiased systems-based approach to examine the relationship between immune responses, flu-induced inflammation, skeletal muscle tissue morphology, muscle function, and full muscle transcriptome. Implicated factors and pathways will be verified utilizing in vitro myoblast and myotube cultures and in vivo serum and/or cytokine/chemokine injections. The overarching scientific premise of this proposal is based on our published study that demonstrated increased muscle atrophy during flu infection with aging. We believe that lingering systemic inflammation in aged individuals during flu infection and increased muscle sensitivity to this inflammation contributes to increased muscle-localized inflammation, cellular infiltration, and muscle atrophy. Our integrated approach will test this hypothesis, while also generating additional unbiased hypotheses based on transcriptomics and statistical modeling to determine the driving mechanism behind flu-induced muscle atrophy. Understanding mechanisms responsible will guide preventative and therapeutic measures. Furthermore, this study has significant potential to discover high impact translational findings that will improve care for flu-infected elderly and help them maintain their independence later in life.

项目摘要流感（流感）感染是老年人死亡的主要原因。此外，重要的是，这是一个共同的但未被充分认识到是导致老年人发病率过高、残疾和丧失独立性的因素。我们最近发表的证据首次证明了流感感染和流动性下降之间的病理生理学联系使用小鼠模型的性能。尽管活跃的流感感染局限于肺部，但有明显的肌肉中的功能减退和分子改变，伴随肌肉炎症的上调，萎缩基因和肌肉生长的正调节因子的下调。重要的是，流感感染的影响这些分子的变化和整体功能的下降是更明显的，并随着年龄的增长而延长。我们这项R21提案的主要目标是确定将肺流感感染与肌肉健康和功能能力。由于我们的数据不支持骨骼肌的直接病毒感染，我们相信全身因素是流感引起的肌肉萎缩的根源。因此，产生全身性与流感相当的反应假设也会导致肌肉随着年龄的增长而损失。因此，本提案将深入研究不仅是流感引起的肌肉萎缩背后的机制，炎症和/或感染引起的肌病和衰老引起的残疾。确定潜在机制在流感引起的肌肉萎缩背后，我们将采用一种无偏见的基于系统的方法来研究免疫应答、流感诱导的炎症、骨骼肌组织形态学、肌肉功能和完整的肌肉转录组。利用体外成肌细胞验证相关因素和途径以及肌管培养和体内血清和/或细胞因子/趋化因子注射。总体科学这一建议的前提是基于我们发表的研究，该研究表明，在流感期间肌肉萎缩增加感染老化。我们认为，在流感感染期间，增加的肌肉对这种炎症的敏感性导致增加的肌肉局部炎症、细胞炎症、炎症细胞浸润和炎症细胞浸润。浸润和肌肉萎缩。我们的综合方法将测试这一假设，同时也产生额外的基于转录组学和统计建模的无偏假设，以确定驱动机制流感导致的肌肉萎缩了解责任机制将指导预防和治疗措施。此外，这项研究具有重大的潜力，发现高影响翻译，这些发现将改善对感染流感的老年人的护理，并帮助他们在以后的生活中保持独立。