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.

项目概要/摘要 Ural 博士是 Donna Farber 博士实验室的博士后科学家，致力于识别免疫系统的变化 随着老龄化肺系统和肺相关淋巴结的人口统计数据在许多地区发生变化。 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负担。 研究表明，肺功能在三十岁后开始下降，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而导致人类衰老。 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）对免疫系统老化的影响尚未得到充分研究。 巨噬细胞是执行特殊组织功能的多样化细胞群。 空气污染等暴露会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作出反应以保持组织稳态的细胞类型之一 然而，由于巨噬细胞的可用性有限，对人体组织的巨噬细胞研究非常有限。 阐明衰老的肺巨噬细胞免疫力如何随环境变化非常重要。 唐娜博士，以开发针对最近遇到的病原体的有效免疫疗法。 法伯的实验室与当地采购组织进行了独特的合作，从那里获取多个组织站点 我们的研究表明，碳颗粒会在人类肺部积聚。 引流淋巴结（LLN）随着年龄的增长而变化，而相应的肠系膜淋巴结（MLN）则没有变化。 颗粒物包含在淋巴结巨噬细胞的子集中，这导致 该巨噬细胞亚群中细胞因子的产生受损，导致活化和吞噬作用减少。 此外，老化 LLN 的这些改变会破坏 B 细胞滤泡的完整性，导致淋巴管减少，而这并不是 我们的中心假设是，环境颗粒物包含在特定的颗粒物中。 肺巨噬细胞亚群由于其独特的定位以及这些颗粒，导致老化的肺巨噬细胞亚群 巨噬细胞的转录谱发生了改变，导致呼吸道免疫反应受损。 该建议是 1) 评估人类肺巨噬细胞群的功能特性 2）评估老化肺的吞噬和迁移潜力。 巨噬细胞以及巨噬细胞如何应对最近遇到的大气颗粒物 该职业奖项将为乌拉尔博士提供提升培训和经验的机会。 使用双光子成像、CODEX 成像等创新方法来研究巨噬细胞衰老 该奖项将为博士提供全面的高维转录组学数据的计算分析。 乌拉尔未来将成为一名独立的肺部研究员，研究衰老在组织特异性中的作用 免疫调节。