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。 为了避免累积性损伤，肺部驻留细胞依赖于应激反应的稳定平衡 然而，在某个临界点（不可逆点），衰老最终会破坏这些控制。 导致氧化环境增加和不可逆损伤的机制。我们的数据表明 老年人（人类和小鼠）的肺组织具有高炎症和氧化应激基线，导致 驱动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 [e.g.,结核病（TB）和2019冠状病毒病（COVID-19）]。定义这些变化的时间和方式 在细胞和分子水平上发生在肺中对于理解与年龄相关的肺特异性 病理学和衰老。我们的数据将线粒体功能障碍与累积的氧化应激联系起来， 老年人的肺，其中减少肺氧化应激的干预措施可以逆转对呼吸道疾病的易感性。 疾病线粒体自噬（mitochondrial autophagy）也在此阶段受损，导致细胞凋亡增加。 氧化应激物在细胞中的积累。我们现在假设衰老相关的线粒体 功能障碍和受损的线粒体自噬是肺对分枝杆菌控制崩溃的核心。使用 广泛接受的小鼠衰老模型，本申请旨在确定是否与衰老相关的线粒体 功能障碍驱动肺细胞中的氧化应激增加，产生允许的肺环境， 呼吸道感染，如结核分枝杆菌，结核病的病原体。完成F99阶段 将通过提供强大的知识和技术支持，促进我向博士后阶段（K 00阶段）的过渡 培训，因此，有助于我成为一个独立的研究人员在生物学的目标， 老龄化领域。

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.