Elucidate the adverse impact of mitochondria-induced oxidative stress in molecular and cellular determinants in the aging lung, driving susceptibility to Mycobacterium tuberculosis infection

项目摘要 到2050年，老龄化人口将翻一番，达到20亿。自然肺老化与渐进性变化有关 在分子和生理水平上，导致肺功能下降和免疫反应受损。 为了避免累积损伤，驻肺细胞依赖于压力反应的强健的动态平衡。 然而，在某个临界点(S)(不归路点)，衰老最终压倒了这些控制 导致氧化环境增加和不可逆转损害的机制。我们的数据表明 老年人(人类和小鼠)的肺组织具有较高的炎症和氧化应激基线，导致 导致宿主对呼吸道感染易感性的关键先天可溶性和细胞成分的功能障碍 [例如，结核病和2019年冠状病毒病(新冠肺炎)]。定义这些更改的时间和方式 在细胞和分子水平上发生在肺中是理解与年龄相关的肺的特异性的关键 病理和衰老的一般情况。我们的数据将线粒体功能障碍与累积氧化应激联系在一起 老年人的肺部，在那里减少肺部氧化应激的干预可以逆转对呼吸系统的易感性 疾病。有丝分裂吞噬(线粒体自噬)在这个阶段也受到损害，导致增加 氧化应激源在细胞内的积累。我们现在假设与衰老相关的线粒体 功能障碍和丝裂原吞噬功能受损是分枝杆菌肺部控制崩溃的核心。使用 公认的小鼠衰老模型，这项应用旨在确定与衰老相关的线粒体 功能障碍导致肺细胞氧化应激增加，为 呼吸道感染，如肺结核的病原体--结核分枝杆菌。完成F99阶段 将通过提供强大的智力和技术支持，促进我过渡到博士后阶段(K00阶段) 培训，并因此有助于我的目标，成为一名独立的研究人员在生物学 老化字段。

PROJECT ABSTRACT The aging population will double to 2 billion by 2050. Natural lung aging is associated with progressive changes at molecular and physiological levels, causing a decline in lung function and impaired immunological responses. To avoid cumulative damage, lung-resident cells rely on a robust homeostatic balance of stress response pathways; however, at a certain tipping point(s) (point of no return), aging finally overwhelms these control mechanisms leading to an increased oxidative environment and irreversible damages. Our data indicate that lung tissue in the elderly (in humans and mice) has high inflammation and oxidative stress baselines, leading to dysfunction of critical innate soluble and cellular components driving host susceptibility to respiratory infections [e.g., Tuberculosis (TB) and Coronavirus disease 2019 (COVID-19)]. Defining when and how these changes occur in the lung at the cellular and molecular levels is critical to understanding age-associated lung-specific pathologies and aging in general. Our data link mitochondrial dysfunction to cumulative oxidative stress in the lung of the elderly, where interventions that reduce lung oxidative stress can reverse susceptibility to respiratory diseases. Mitophagy (mitochondrial autophagy) is also impaired at this stage, resulting in increased accumulation of oxidative stressors in cells. We now hypothesize that aging-associated mitochondrial dysfunction and impaired mitophagy is central to the collapse in pulmonary control of mycobacteria. Using the well-accepted mouse model of aging, this application aims to determine whether aging-associated mitochondrial dysfunction drives increased oxidative stress in lung cells, generating a permissive lung environment for respiratory infections such as Mycobacterium tuberculosis, the causative agent of TB. Completing the F99 phase will facilitate my transition to the postdoctoral phase (K00 phase) by providing robust intellectual and technical training and, consequently, contributing to my goal of becoming an independent researcher in the biology of Aging field.