Impact of Environmental Exposures on Lung Immunity over Age

随着年龄的增长，环境暴露对肺部免疫力的影响

• 批准号: 10740394
• 负责人: Basak Burcu Ural
• 金额: $ 12.53万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740394
• 关键词: Activities of Daily Living; Affect; Age; Aging; Air Pollution; Alveolar Macrophages; Atmosphere; Award; B-Lymphocytes; Biology of Aging; Brain Death; Carbon; Cells; Collaborations; Computer Analysis; Coronavirus; Data; Elderly; Environment; Environmental Exposure; Environmental Impact; Exposure to; Flow Cytometry; Future; Gene Expression Profile; Healthcare; Homeostasis; Human; Image; Imaging technology; Immune; Immune response; Immune system; Immunity; Immunotherapy; Impairment; Inflammation; Inflammatory Response; Influenza; Life; Lung; Lung diseases; Lymphatic; Macrophage; Malignant Neoplasms; Mentors; Mus; Organ Donor; Organism; Paper; Particulate; Particulate Matter; Patients; Persons; Phagocytosis; Population; Population Heterogeneity; Postdoctoral Fellow; Predisposition; Production; Property; Research Personnel; Respiratory Disease; Respiratory Tract Diseases; Respiratory Tract Infections; Role; Scientist; Severity of illness; Shapes; Site; Structure of parenchyma of lung; Tissues; Training; Transgenic Mice; Virus Diseases; Work; age related; aged; airway immune response; brain tissue; care burden; career; cell type; confocal imaging; cytokine; demographics; design; draining lymph node; environmental particulate; experience; high dimensionality; human tissue; immunoregulation; influenza infection; innovation; lymph nodes; lymphatic drainage; mesenteric lymph node; migration; mortality; mouse model; neoplastic; particle; pathogen; pulmonary function; respiratory pathogen; senescence; single cell sequencing; transcriptome; transcriptomics; two-photon; uptake

PROJECT SUMMARY/ABSTRACT Dr. Ural is a Postdoctoral Scientist in Dr. Donna Farber’s lab working on identifying alterations in the immune system of aging lung and lung-associated lymph nodes. As demographics are changing across many parts of the world, age related lung diseases are expected to become a major healthcare burden. Recent studies have shown that lung function starts to decline after third decade of life, and this leads to increased mortality rate in elderly people due to infectious and non-infectious lung diseases. Human aging is shaped with prolonged exposure to the environment; however, due to limited availability of healthy pulmonary tissues, the impact of environmental exposures (e.g., air pollution) to the aging immune system is not well studied. Macrophages are a diverse population of cells that perform specialized tissue functions. Environmental exposures such as air pollution can have direct effect on the local immune system and pulmonary macrophages are among the first cell types to respond to all the environmental exposures for tissue homeostasis and surveillance. However, macrophage studies in human tissues are very limited due to limited availability of such tissues. It is important to elucidate how aging pulmonary macrophage immunity changes with environmental exposures in order to develop effective immune therapies to recently encountered pathogens. Dr. Donna Farber’s lab has a unique collaboration with a local procurement organization to obtain multiple tissue sites from healthy brain-dead organ donors. Our studies showed that carbon particulates accumulate in human lung draining lymph nodes (LLN) with age while the corresponding mesenteric lymph nodes (MLNs) show no particulate matter. Carbon particulates are contained within a subset of lymph node macrophages, and this leads to reduced activation and phagocytosis with impaired production of cytokines in this macrophage subset. Moreover, these alterations in aging LLNs disrupt B cell follicle integrity with reduction in lymphatics, which is not observed in MLNs. Our central hypothesis is that the environmental particulates are contained within a specific pulmonary macrophage subset because of its distinct localization and due to these particulates, aging pulmonary macrophages have altered transcriptional profile, with compromised respiratory immune response. The aims of this proposal are 1) Evaluate functional properties of human pulmonary macrophage population that takes up environmental particulates over age. 2) Evaluate the phagocytosis and migration potential of aging pulmonary macrophages and how macrophages with atmospheric particulate matter respond to recently encountered pathogens over age. This career award will give Dr. Ural the opportunity to advance her training and experience on macrophage aging, using innovative approaches such as two-photon imaging, CODEX imaging, and computational analysis of high dimensional transcriptomics data. This award will comprehensively prepare Dr. Ural for her future career as an independent pulmonary researcher studying the role of aging in tissue specific immune regulation.

项目摘要/摘要 乌拉尔（Ural）博士是唐娜·法伯（Donna Farber）博士实验室的博士后科学家，致力于识别免疫力的改变 衰老肺和肺相关淋巴结系统。随着人口统计的变化， 与年龄相关的肺部疾病的世界有望成为重大的医疗保健负担。最近的研究 表明肺功能在生命的第三个十年后开始下降，这导致死亡率提高 老年人由于传染性和非感染性肺部疾病。人衰老的形状长时间 暴露于环境；但是，由于健康肺组织的可用性有限， 衰老免疫系统的环境暴露（例如，空气污染）并不是很好。 巨噬细胞是执行专门组织功能的细胞的潜水群。环境的 诸如空气污染之类的暴露可能会对局部免疫系统和肺巨噬细胞产生直接影响 是最早应对组织内稳态和所有环境暴露的细胞类型之一 监视。但是，由于这种可用性有限，人类组织中的巨噬细胞研究非常有限 组织。重要的是阐明衰老的肺巨噬细胞免疫学如何随环境而变化 暴露是为了开发有效的免疫室，以使最近遇到病原体。唐娜博士 Farber的实验室与当地采购组织进行了独特的合作，以获取多个组织网站 健康的脑死亡器官捐献者。我们的研究表明，碳参与人肺 随着年龄的年龄，相应的肠系膜淋巴结（MLN）的图淋巴结（LLN）显示NO 颗粒物。碳具体物包含在淋巴结巨噬细胞的子集中，这导致 在此巨噬细胞子群中，细胞因子的产生受损而降低活化和吞噬作用。 此外，这些衰老LLN的改变破坏B细胞卵泡完整性，淋巴管的降低，这不是 在MLN中观察到。我们的中心假设是环境组成部分包含在特定的 肺巨噬细胞子群由于其明显的定位，并且由于这些成分，老化的肺部 巨噬细胞的转录特征改变，呼吸免疫反应受损。目的 该建议是1）评估占用人类肺巨噬细胞种群的功能特性 超过年龄的环境组成部分。 2）评估衰老肺的吞噬作用和迁移潜力 巨噬细胞以及与大气特定物质的巨噬细胞如何应对最近遇到的 年龄超过年龄的病原体。该职业奖将使乌拉尔博士有机会提高她的培训和经验 关于巨噬细胞衰老，使用创新方法，例如两光子成像，法典成像和 高维转录组学数据的计算分析。该奖项将全面准备博士。 乌拉尔（Ural 免疫调节。