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

阐明线粒体诱导的氧化应激对衰老肺部分子和细胞决定因素的不利影响，从而导致对结核分枝杆菌感染的易感性

• 批准号: 10560913
• 负责人: Angelica Milagros Olmo-Fontanez
• 金额: $ 3.75万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2023-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10560913
• 关键词: Acute; Affect; Age; Aging; Alveolar; Alveolus; Automobile Driving; Award; Biology of Aging; Biomedical Research; COVID-19; Cells; Chronic; Communicable Diseases; Communication; Communities; Data; Doctor of Philosophy; Elderly; Electron Transport; Environment; Epithelial Cells; Equilibrium; Experimental Designs; Faculty; Fellowship; Functional disorder; Future; Generations; Genus Mycobacterium; Goals; Grant; Health; Health Promotion; Health Sciences; Human; Immune; Immune response; Impairment; In Vitro; Individual; Infection; Inflammation; Inner mitochondrial membrane; Institution; International; Intervention; Laboratories; Latina; Lead; Leadership; Link; Liquid substance; Lung; Lung diseases; Lung infections; Manuscripts; Mentors; Mentorship; Mitochondria; Molecular; Mus; Mycobacterium tuberculosis; Oral; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Peer Review; Phase; Physiological; Physiology; Play; Population; Positioning Attribute; Postdoctoral Fellow; Predisposition; Process; Publishing; Reporting; Research; Research Institute; Research Personnel; Research Project Grants; Respiratory Disease; Respiratory Tract Infections; Role; Science; Scientist; Structure of parenchyma of lung; Students; Techniques; Testing; Texas; Thinking; Time; Training; Translational Research; Tuberculosis; United States; Universities; Woman; Work; Writing; aging population; alveolar epithelium; biological adaptation to stress; career; doctoral student; experience; graduate student; human old age (65+); in vivo; inflammatory milieu; lung pathogen; meetings; minority scientist; mitochondrial autophagy; mitochondrial dysfunction; mouse model; next generation; novel; posters; pre-doctoral; programs; pulmonary function; respiratory; skills; stressor; tenure track

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.

项目摘要 到 2050 年，老龄化人口将翻一番，达到 20 亿。肺部自然衰老与渐进性变化相关 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，肺驻留细胞依赖于应激反应的强大稳态平衡 途径；然而，在某个临界点（不归路），衰老最终会压倒这些控制 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 关键先天可溶性和细胞成分的功能障碍导致宿主对呼吸道感染的易感性 [例如，结核病 (TB) 和 2019 年冠状病毒病 (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部对于了解与年龄相关的肺部特异性至关重要 一般病理学和衰老。我们的数据将线粒体功能障碍与累积氧化应激联系起来 老年人的肺部，减少肺部氧化应激的干预措施可以逆转呼吸道疾病的易感性 疾病。线粒体自噬（线粒体自噬）在此阶段也会受损，导致线粒体自噬增加 细胞内氧化应激物质的积累。我们现在假设与衰老相关的线粒体 功能障碍和线粒体自噬受损是分枝杆菌肺部控制崩溃的核心。使用 作为公认的小鼠衰老模型，该应用旨在确定是否与衰老相关的线粒体 功能障碍会导致肺细胞氧化应激增加，从而为肺细胞创造一个宽松的环境 呼吸道感染，例如结核病病原体——结核分枝杆菌。完成F99阶段 将通过提供强大的智力和技术帮助我过渡到博士后阶段（K00阶段） 培训，从而为我成为生物学独立研究员的目标做出贡献 老化领域。