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.

项目总结/摘要 博士Ural是Donna Farber博士实验室的博士后科学家，致力于识别免疫系统中的改变。 老化的肺和肺相关淋巴结系统。随着人口结构在许多地区的变化， 在世界范围内，与年龄相关的肺部疾病预计将成为主要的医疗保健负担。最近的研究 肺功能在30岁后开始下降，这导致死亡率增加， 老年人由于感染性和非感染性肺部疾病。人类的衰老是由长期的 暴露于环境;然而，由于健康肺组织的可用性有限， 环境暴露（例如，空气污染）对衰老免疫系统的影响还没有得到很好的研究。 巨噬细胞是执行专门组织功能的细胞的多样性群体。环境 空气污染等暴露可对局部免疫系统和肺巨噬细胞产生直接影响。 是最早对所有环境暴露做出反应以实现组织稳态的细胞类型之一， 监视然而，人体组织中的巨噬细胞研究非常有限，这是由于此类巨噬细胞的可用性有限。 组织中阐明衰老肺巨噬细胞免疫如何随环境变化而变化是重要的 为了开发针对最近遇到的病原体的有效免疫疗法，唐娜博士 法伯的实验室与当地采购组织进行了独特的合作，从 健康的脑死亡器官捐赠者我们的研究表明，碳颗粒在人的肺部积累， 引流淋巴结（LLN）随年龄增长而增加，而相应的肠系膜淋巴结（MLN）显示无 颗粒物淋巴结巨噬细胞中含有碳颗粒，这导致 导致该巨噬细胞亚群中细胞因子产生受损的活化和吞噬作用降低。 此外，这些在老化LLN中的改变破坏了B细胞卵泡的完整性，减少了淋巴细胞，这不是正常的。 在MLN中观察。我们的中心假设是，环境颗粒物包含在一个特定的 肺巨噬细胞亚群，因为其独特的定位和由于这些颗粒，老化的肺 巨噬细胞的转录谱改变，呼吸免疫应答受损。的目的 该建议是：1）评估人肺巨噬细胞群体的功能特性， 环境颗粒物2)评估老化肺的吞噬和迁移能力 巨噬细胞以及巨噬细胞与大气颗粒物如何应对最近遇到的情况 随着年龄的增长，这个职业奖将使乌拉尔博士有机会提高她的培训和经验 巨噬细胞老化，使用创新的方法，如双光子成像，CODEX成像， 高维转录组学数据的计算分析。该奖项将全面准备博士。 乌拉尔为她未来的职业生涯作为一个独立的肺部研究人员研究衰老的作用，在组织特异性 免疫调节