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.

项目摘要 预计在未来40年内，老年人口将翻一番，因此与衰老有关的疾病也将增加。 很可能成为一个重大的医疗负担。肺部疾病，包括肺气肿、慢性阻塞性肺疾病 肺部疾病和间质性肺病，以及一般肺部病理学，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 其根本原因和机制仍不明确。重要的是，衰老与许多 肺生理学和肺免疫力的变化，包括肺活量降低、粘膜纤毛减少 清除，并增加对细菌和病毒感染的易感性。肺生理变化， 病原体易感性可能相关;然而，关于这些年龄相关的影响知之甚少。 免疫系统对肺的监视的生理变化。识别这些细胞中的分子变化 随着年龄的增长，可以导致新的治疗干预措施，以帮助保护老化的肺， 发病率我们建立了一种新的人体组织资源， 以及来自所有年龄的器官供体的粘膜组织，所述年龄包括直至生命的第9个十年的所有成年年龄。 重要的是，我们获得了肺、肺相关和外周淋巴组织，从而能够对衰老进行新的研究- 几十年来的变化。我们的中心假设是，随着年龄的增长， 免疫监视和保护免受肺驻留免疫细胞和肺相关淋巴结的侵害， 导致肺细胞完整性降低和对损伤的敏感性增加。在拟议的研究中，我们将 采取多学科方法研究肺免疫系统与肺之间的相互作用 作为年龄的函数。在aim 1中，我们将确定肺驻留免疫细胞和肺相关免疫细胞如何在肺内表达。 淋巴结（LN）随年龄变化。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卵泡的功能活性。在目标2中，我们将使用真实的时间光学成像 以确定年龄对肺泡-毛细血管流体屏障质量的影响， 肺泡上皮线粒体功能，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 在所有肺细胞中的基因表达程序，使用单细胞RNA-Seq评估基因表达程序， 定义肺上皮细胞、内皮细胞、先天性和适应性免疫细胞将被改变， 这些变化。这项研究将揭示人类肺部免疫学和生理学的新见解 以及使个体易患呼吸道疾病增加的年龄相关变化的机制。