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: 10620758
• 负责人: GR Scott Budinger
• 金额: $ 192.72万
• 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/10620758
• 关键词: Acceleration; Address; Affect; Age; Aging; Alveolar Macrophages; Animals; Award; Binding; Biological; Biology of Aging; Brain; Caenorhabditis elegans; Cause of Death; Cells; Cessation of life; Chronic Kidney Failure; Chronology; Cognitive deficits; Communicable Diseases; Complex; Data; Data Set; Dementia; Disease; Elderly; Electron Transport; Endocrine; Environmental Pollution; Event; Friends; Functional disorder; Geroscience; Healthcare; Hospitals; Human Biology; Immobilization; Immune; Impaired cognition; Impairment; Individual; Infection; Influenza A virus; Injury; Intervention; Laboratories; Longevity; Lung; Macrophage; Metabolic; Microglia; Mitochondria; Mitochondrial Electron Transport Complex I; Modeling; Modernization; Molecular Conformation; Morbidity - disease rate; Motor; Mus; Muscle function; Mutant Strains Mice; Myocardial Infarction; Organ; Pathway interactions; Play; Pneumonia; Process; Productivity; Protein Biosynthesis; Proteins; Proteome; Proteomics; Publishing; Pulmonary Inflammation; 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; biological adaptation to stress; clinically relevant; cognitive function; end of life; environmental stressor; frailty; healthspan; improved; influenza A pneumonia; inhibitor; lung injury; lung repair; mitochondrial metabolism; older men; older patient; overtreatment; pandemic influenza; pneumonia treatment; programs; promote resilience; 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.

项目概要_总体 老年科学假说基于这样的观察：生命临近终点时健康寿命会下降 通常表现为单一与年龄相关的疾病，随后迅速积累与年龄相关的疾病 在相对较短的时间内出现并发症。根据这一假设，治疗这些病症中的任何一种 如果不治疗衰老的基本生物学，只会导致其被另一种生物学所取代。发现 针对衰老生物学以提高复原力和减少虚弱的疗法解决了老年科学问题 假设，但仅根据实际年龄进行这些治疗将不可避免地导致 在过度治疗中。虽然肺炎在老年人中更常见且更严重，但大多数老年患者患有 获得现代医疗保健使他们能够在疾病中幸存下来。然而，在出院后的一年里，这些老年人 肺炎幸存者患年龄相关疾病（包括持续性肺病）的风险增加 损伤、骨骼肌功能障碍导致行动不便、痴呆和认知障碍。像这样， 肺炎是复合发病率的一个门户，限制了生命临终时的健康寿命。我们因此 之所以采取针对衰老生物学的干预措施以改善修复并提高恢复能力 在老年人从肺炎或其他环境压力因素恢复期间将产生广泛的影响。 蛋白质稳态是指细胞控制浓度、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。在该奖项的第一轮中， PPG 调查人员已生成大量已发表的初步数据，支持中央 该 PPG 的假设是，高龄与肺炎恢复受损有关，以及 针对线粒体电子传递链复合物 I 的代谢干预可以逆转这些 通过综合应激反应和 ATF4 恢复蛋白质稳态来改变。为了解决这个问题 衰老的基本问题，项目研究人员将重点关注感染后的组织恢复 小鼠甲型流感病毒，一种可以严格应用于整个生命周期的临床相关模型 它在可以在实验室研究的时间范围内概括了人类生物学。我们将测试这个 三个相互关联的项目/目标的假设： 目标 1. 确定与年龄相关的肺泡巨噬细胞修复功能损伤是否可以 复合物 I 抑制剂通过 ISR 和 ATF4 短暂低水平抑制电子传递，从而逆转这种现象。 目标 2. 确定复合物 I 的线粒体电子传递在整个生命周期中是否受到抑制 导致甲型流感肺炎后与年龄相关的恢复障碍。 目的 3. 确定老年人骨骼清道夫受体功能是否受损 复合物 I 的抑制剂可以通过 ISR 和 ATF4 逆转肌肉巨噬细胞和小胶质细胞 改善肺炎后的运动和认知功能。