Disordered Proteostasis as a Driver of Disease in the Aging Lung

蛋白质稳态紊乱是衰老肺疾病的驱动因素

• 批准号: 10197736
• 负责人: GR Scott Budinger
• 金额: $ 196.49万
• 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/10197736
• 关键词: Address; Affect; Age; Aging; Alveolar Macrophages; Animals; Award; Binding; Biological; Biology of Aging; Caenorhabditis elegans; Cause of Death; Cells; Cessation of life; Chronic; Chronology; Cognitive; Cognitive deficits; Communicable Diseases; Complex; Data; Data Set; Dementia; Disease; Elderly; Electron Transport; Endocrine; Event; Friends; Functional disorder; Geroscience; Healthcare; Hospitals; Human Biology; Immune; Impaired cognition; Impairment; Individual; Infection; Influenza A virus; Injury; Intervention; Kidney; Laboratories; Longevity; Lung; Lung Inflammation; Metabolic; Microglia; Mitochondria; Mitochondrial Electron Transport Complex I; Modeling; Modernization; Molecular Conformation; Morbidity - disease rate; Motor; Mus; Muscle function; Mutant Strains Mice; Myocardial; Pathway interactions; Play; Pneumonia; Process; Productivity; Protein Biosynthesis; Proteins; Proteome; Proteomics; Publishing; Recovery; Regulatory T-Lymphocyte; Research Personnel; Respiratory Failure; Risk; Role; Scientist; Signal Transduction; Skeletal Muscle; Stress; Survivors; System; Testing; Time; Tissues; Virus Diseases; activating transcription factor 4; age related; aged; base; biological adaptation to stress; clinically relevant; cognitive function; end of life; environmental stressor; frailty; healthspan; improved; influenza A pneumonia; inhibitor/antagonist; lung injury; macrophage; man; mitochondrial metabolism; older patient; overtreatment; pandemic influenza; programs; proteostasis; receptor function; repair function; repaired; resilience; response; scavenger receptor; seasonal influenza; skeletal muscle wasting; targeted treatment; trafficking; transcriptomics

PROJECT SUMMARY_OVERALL The Geroscience hypothesis is based on the observation that healthspan decline toward the end of life often presents with a single age-related illness that is followed by rapid accumulation of age-related complications over a relatively short period. According to this hypothesis, treating any one of these conditions without treating the fundamental biology of aging will only result in its substitution by another. The discovery of therapies that target aging biology to improve resilience and reduce frailty address the geroscience hypothesis, but administering these therapies based exclusively on chronological age will inevitably result in overtreatment. While pneumonia is more common and more severe in the elderly, most older patients with access to modern health care survive their illness. However, in the year after hospital discharge these older pneumonia survivors have an increased risk of developing age-related disorders including persistent lung injury, skeletal muscle dysfunction leading to immobility, dementia, and cognitive impairment. As such, pneumonia is a gateway for the compounding morbidity that limits healthspan at the end of life. We therefore reason that interventions that target aging biology to improve repair and promote resilience administered during recovery from pneumonia or other environmental stressors in the elderly will have broad impact. Proteostasis refers to the dynamic process by which cells control the concentration, conformation, binding interactions, and stability of individual proteins making up the proteome. In the first cycle of this award, the PPG investigators have generated substantial published and preliminary data supporting the central hypothesis of this PPG that advanced age is associated with impaired recovery from pneumonia, and metabolic interventions targeting complex I of the mitochondrial electron transport chain can reverse these changes by restoring proteostasis through the integrated stress response and ATF4. To address this fundamental question in aging, the project investigators will focus on tissue recovery after infection with the influenza A virus in mice, a clinically relevant model that can be rigorously applied across the entire lifespan and which recapitulates human biology on a time frame that can be studied in the laboratory. We will test this hypothesis in three interrelated projects/aims: Aim 1. To determine whether age-related impairments in the reparative function of alveolar macrophages can be reversed by transient low level inhibition of electron transport with complex I inhibitors via the ISR and ATF4. Aim 2. To determine whether inhibition of mitochondrial electron transport at complex I over the lifespan drives the age related impairment in recovery after influenza A pneumonia. Aim 3. To determine whether the impaired scavenger receptor function of aged resident skeletal muscle macrophages and microglia can be reversed by inhibitors of complex I via the ISR and ATF4 to improve motor and cognitive function after pneumonia.

项目summary_overall GEROSCIENCE假设是基于这样的观察结果，即HealthSpan在生命的尽头下降 通常出现与年龄相关的疾病，随后是与年龄相关的迅速积累 并发症在相对较短的时间内。根据这一假设，治疗这些条件中的任何一种 不治疗衰老的基本生物学，只会导致另一个人的替代。发现 靶向衰老生物学以提高弹性并减少脆弱的疗法的解决方案 假设，但仅根据年代年龄的年龄进行这些疗法，将不可避免地导致 在过度治疗中。尽管肺炎在老年人中更为普遍，更严重，但大多数老年患者 获得现代卫生保健能够幸免于他们的疾病。但是，在住院后的一年这些年龄较大 肺炎幸存者的风险增加了与年龄有关的疾病，包括持续性肺 损伤，骨骼肌功能障碍导致不动，痴呆和认知障碍。像这样， 肺炎是限制生命尽头的健康状况的复杂发病率的门户。因此，我们 针对衰老生物学的干预措施以改善维修和促进弹性的原因 在从肺炎或其他环境压力源中恢复期间，老年人将产生广泛的影响。 蛋白质量是指细胞控制浓度，构象，结合的动态过程 构成蛋白质组的单个蛋白质的相互作用和稳定性。在该奖项的第一个周期中， PPG调查人员已经生成了大量已发布和初步数据，支持了中央 该PPG的假设是，高龄与从肺炎恢复的恢复受损有关 靶向线粒体电子传输链I复合物I的代谢干预措施可以扭转这些 通过综合应力响应和ATF4恢复蛋白质的变化。解决这个问题 衰老中的基本问题，项目调查人员将专注于感染后的组织恢复 小鼠中的流感病毒，这是一种临床相关模型，可以在整个生命周期中严格应用和 这在可以在实验室中研究的时间范围内概括了人类的生物学。我们将测试这个 三个相互关联的项目/目的的假设： 目标1。确定与年龄相关的损伤在肺泡巨噬细胞的修复功能中是否可以 通过通过ISR和ATF4对电子传输对电子传输的瞬时低水平抑制作用逆转。 目的2。确定在寿命上是否抑制复合物在复合物上的线粒体传输 肺炎流感后，驱动与年龄相关的恢复损害。 目标3。确定老年居民骨骼的清道夫受体功能受损 肌肉巨噬细胞和小胶质细胞可以通过ISR和ATF4的复合物抑制剂逆转 改善肺炎后运动和认知功能。