Disordered Proteostasis as a Driver of Disease in the Aging Lung

描述（由申请人提供）：肺部老化导致老龄化人口失去弹性和脆弱，损害健康寿命-减少免于残疾，疼痛和独立的持续时间。改善健康寿命和减少老龄化带来的社会和经济负担的干预策略需要针对可塑系统的新方法，这些系统可以提高弹性，减少老化肺部对病原体和其他环境因素的脆弱性。蛋白质稳态是指细胞通过调节网络系统控制组成蛋白质组的单个蛋白质的浓度、构象、结合相互作用和位置的动态过程。在模式生物中，细胞中蛋白质平衡网络的功能障碍是衰老表型和衰老过程中衰退的共同最终途径；然而，测量哺乳动物肺部这些变化和/或检查其对器官生理学影响的生物学相关技术一直缺乏。该PPG的研究人员开发了新的基于发光和质谱的技术来测量肺部的蛋白质平衡，他们使用这种技术来检查衰老和感染甲型流感病毒期间肺部蛋白质平衡网络的功能，甲型流感病毒是肺损伤的临床重要模型。季节性和大流行性甲型流感感染在老年人中造成不成比例的发病率和死亡率。严重感染导致双侧肺浸润和低氧血症，这是急性呼吸窘迫综合征（ARDS）的定义，这是每年2万至5万甲型流感感染患者死亡的主要原因。在三个高度整合的项目中，项目负责人使用该系统来探测老化过程中蛋白质平衡网络的脆弱性

DESCRIPTION (provided by applicant): The aging lung contributes to the loss of resiliency and frailty in the aging population that impairs the healthspan--reducing the duration of freedom from disability, pain and independence. Interventional strategies to improve healthspan and reduce the social and economic burdens of aging require novel approaches targeting malleable systems that improve resiliency and reduce frailty of the aging lung in response to pathogens and other environmental agents. Proteostasis refers to the dynamic process by which cells control the concentration, conformation, binding interactions, and location of individual proteins making up the proteome through a system of regulated networks. Dysfunction in the proteostasis networks in the cell is a common final pathway in aging phenotypes and declines during aging in model organisms; however, biologically relevant techniques to measure these changes in the mammalian lung and/or examine their consequences for organ physiology have been lacking. The investigators in this PPG have developed novel luminescence- and mass-spectroscopy-based techniques, to measure proteostasis in the lung, which they use to examine the function of the proteostasis networks in the lung during aging and during infection with the influenza A virus, a clinically important model of lung injury. Seasonal and pandemic influenza A infection cause disproportionate morbidity and mortality in older individuals. Severe infection results in the bilateral pulmonary infiltrates and hypoxemia that define the Acute Respiratory Distress Syndrome (ARDS), which is the primary cause of the 20,000-50,000 deaths in patients with influenza A infection each year. The Project Leaders use this system to probe the frailty of the proteostasis networks during aging in three highly integrated Projects and Cores. Project 1 will test the hypothesis that replacement of the tissue-resident alveolar macrophage pool with bone marrow derived alveolar macrophages over the lifespan impairs proteostasis to increase the susceptibility to influenza A infection in aged mice. Project 2 will tst the hypothesis that reducing mitochondrial respiratory chain capacity promotes epithelial proteostasis to attenuate influenza A virus-induced lung injury during aging. Project 3 will test the hypothesis that the enhanced susceptibility of aged, influenza A infected mice to skeletal muscle dysfunction results from an altered balance between signaling from the lung that disrupts proteostasis and signaling from the lung that induces a protective heat shock response. The Project Leaders combine genetic and pharmacologic interventions predicted to enhance or impair proteostatic function in aging mice before and after infection with the influenza A virus with sophisticated assessments of the function of the proteostasis networks (Core B) and lung and skeletal muscle physiology (Core C) to establish causal links between aging, proteostasis, and lung and skeletal muscle dysfunction in a mammalian system, providing important mechanistic and therapeutic insights into human aging.