Immunobiology and alveolar physiology of the aging lung

衰老肺的免疫生物学和肺泡生理学

• 批准号: 10093125
• 负责人: Jahar Bhattacharya
• 金额: $ 64.37万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10093125
• 关键词: Acute Lung Injury; Adult; Adult Respiratory Distress Syndrome; Age; Aging; Alveolar; Alveolar Macrophages; Bacterial Infections; Blood; Blood capillaries; Cell Communication; Cells; Chronic Obstructive Airway Disease; Dendritic Cells; Disease; Elderly; Endothelial Cells; Endothelium; Epithelial; Epithelial Cells; Fibroblasts; Flow Cytometry; Frequencies; Gap Junctions; Gene Expression; Healthcare; Human; Image; Immune; Immune system; Immunity; Immunobiology; Immunofluorescence Immunologic; Immunologic Surveillance; Immunology; Incidence; Individual; Inflammation; Inflammatory; Interstitial Lung Diseases; Kinetics; Lead; Life; Liquid substance; Lung; Lung diseases; Lymphocyte; Lymphoid Tissue; Malignant Neoplasms; Mitochondria; Molecular; Molecular Profiling; Mucociliary Clearance; Mucous Membrane; Organ Donor; Paracrine Communication; Peripheral; Peroxides; Physiological; Physiology; Population; Predisposing Factor; Predisposition; Process; Proteins; Pulmonary Edema; Pulmonary Emphysema; Pulmonary Pathology; T memory cell; T-Lymphocyte; Time; Tissues; Virus Diseases; Vital capacity; age effect; age related; aged; alveolar epithelium; cell motility; cell type; fluorescence imaging; high dimensionality; human imaging; human tissue; imaging platform; imaging study; in vivo imaging; infancy; insight; interdisciplinary approach; lung imaging; lung injury; lymph nodes; macrophage; novel; novel therapeutic intervention; optical imaging; pathogen; programs; quantum; single-cell RNA sequencing; tissue resource; transcriptome

Project Summary The elderly population is expected to double in the next 40 years, and therefore aging-related diseases are likely to become a major healthcare burden. Lung diseases, including emphysema, chronic obstructive pulmonary disease, and interstitial lung disease, and general lung pathologies including acute lung injury (ALI) and the associated acute respiratory distress syndrome (ARDS), increase dramatically in the elderly, although the underlying causes and mechanisms remain undefined. Importantly, aging is associated with a number of changes in lung physiology and lung immunity, including a decreased vital capacity, decreased mucociliary clearance, and increased susceptibility to both bacterial and viral infections. Changes in lung physiology and pathogen susceptibility may be related; however, there is little known regarding the impact of these age-related physiologic changes on surveillance of the lung by the immune system. Identifying molecular changes in these processes with age can lead to new therapeutic interventions to help protect the aging lung and reduce disease incidence. We have established a novel human tissue resource where we obtain multiple lymphoid and mucosal tissues from organ donor of all ages, including all ages of adulthood up to the 9th decade of life. Importantly, we obtain lungs, lung-associated and peripheral lymphoid tissues, enabling novel study of aging- associated changes over a continuum of decades. Our central hypothesis is that with age, there is decreased immune surveillance and protection both from lung-resident immune cells and lung-associated lymph nodes, resulting in decreased lung cell integrity and increased susceptibility to damage. In the proposed study, we will take a multi-disciplinary approach to study the interaction between the lung immune system and lung epithelium as a function of age. In aim 1 we will identify how lung resident immune cells and lung-associated lymph nodes (LN) alter with age. We will use high dimensional cellular and molecular profiling using high parameter flow cytometry and whole transcriptome profiling to assess changes in immune cell populations, and immunofluorescence imaging to determine the frequency and localization of lung-resident immune cells, and the functional activity of LN through examination of LN follicles. In aim 2, we will use real time optical imaging of the human lung to determine the effect of age on the quality of the alveolar-capillary fluid barrier, mitochondrial function in the alveolar epithelium, and the extent to which resident AMs maintain gap junctional and paracrine communication with the alveolar epithelium. In aim 3, we will define the age-drive gene expression program in all lung cells, using single cell RNA-Seq to assess how gene expression programs that define lung epithelial cells, endothelial cells, innate and adaptive immune cells will be altered and the kinetics of these alterations. The proposed studies will reveal new insights into human lung immunology and physiology and mechanisms for age-associated changes that predispose individuals to increased respiratory disease.

项目概要 预计未来 40 年老年人口将增加一倍，因此与衰老相关的疾病将增加 可能成为主要的医疗负担。肺部疾病，包括肺气肿、慢性阻塞性肺病 肺部疾病、间质性肺疾病以及一般肺部病变，包括急性肺损伤 (ALI) 以及相关的急性呼吸窘迫综合征（ARDS）在老年人中急剧增加，尽管 根本原因和机制仍未明确。重要的是，衰老与许多因素有关 肺生理和肺免疫力的变化，包括肺活量下降、粘液纤毛减少 清除，并增加对细菌和病毒感染的易感性。肺部生理学的变化和 可能与病原体的易感性有关；然而，人们对这些与年龄相关的影响知之甚少。 免疫系统监视肺部的生理变化。识别这些中的分子变化 随着年龄的增长过程可以导致新的治疗干预措施，以帮助保护老化的肺部并减少 疾病发生率。我们建立了一种新型人体组织资源，从中获得多种淋巴组织 以及来自所有年龄段器官捐献者的粘膜组织，包括成年期直至九十岁的所有年龄段。 重要的是，我们获得了肺、肺相关组织和外周淋巴组织，从而能够进行衰老的新研究 数十年来的相关变化。我们的中心假设是，随着年龄的增长， 来自肺驻留免疫细胞和肺相关淋巴结的免疫监视和保护， 导致肺细胞完整性下降并增加对损伤的易感性。在拟议的研究中，我们将 采用多学科方法研究肺免疫系统与肺之间的相互作用 上皮细胞作为年龄的函数。在目标 1 中，我们将确定肺驻留免疫细胞和肺相关细胞如何 淋巴结 (LN) 随着年龄的增长而变化。我们将使用高维细胞和分子分析 参数流式细胞术和全转录组分析以评估免疫细胞群的变化，以及 免疫荧光成像以确定肺驻留免疫细胞的频率和定位，以及 通过检查 LN 滤泡了解 LN 的功能活动。在目标 2 中，我们将使用实时光学成像 人肺的变化，以确定年龄对肺泡毛细血管液体屏障质量的影响， 肺泡上皮中的线粒体功能，以及驻留 AM 维持间隙连接的程度 以及与肺泡上皮的旁分泌通讯。在目标 3 中，我们将定义年龄驱动基因 使用单细胞 RNA-Seq 评估基因表达程序如何在所有肺细胞中进行表达程序 定义肺上皮细胞、内皮细胞、先天性和适应性免疫细胞将发生改变，动力学 这些改变。拟议的研究将揭示人类肺免疫学和生理学的新见解 以及与年龄相关的变化的机制，这些变化使个体容易患上呼吸道疾病。