Airway Epithelial Resilience to Environmental/Oxidative Threats: Intersection with Type-2 Biology and Racial Inequity

气道上皮对环境/氧化威胁的抵抗力：与 2 型生物学和种族不平等的交叉

• 批准号: 10480761
• 负责人: Alexander James Schuyler
• 金额: $ 4.34万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10480761
• 关键词: Address; Adult; Adult asthma; Affect; Air; Air Pollutants; Air Pollution; Antioxidants; Arachidonate 15-Lipoxygenase; Area; Asthma; Autophagocytosis; Bioinformatics; Biological; Biology; Black American; Black Populations; Black race; Cell Death; Cells; Cellular Stress; Cellular biology; Cessation of life; Clinical; Communities; Data; Disease; Environment; Environmental Hazards; Environmental Health; Environmental Risk Factor; Epidemiology; Epithelial; Epithelial Cells; Exposure to; Fellowship; Foundations; Functional disorder; Gene Expression; Genes; Geography; Glutathione Metabolism Pathway; Goals; Human; Hyperplasia; Immune response; Impairment; In Vitro; Inflammation; Institutes; Institutional Racism; Intervention; Knowledge; Link; Lipoxygenase 1; Lung; Measures; Mitochondria; Mitochondrial DNA; Molecular; Morbidity - disease rate; Mucous body substance; Nasal Epithelium; Neighborhoods; Outcome; Oxidative Stress; Oxides; Pathologic; Pathologic Processes; Pathway interactions; Patients; Phosphatidylethanolamine Binding Protein; Phospholipids; Physiological; Play; Predisposition; Process; Public Health; Public Health Education; Pulmonology; Reactive Oxygen Species; Reduced Glutathione; Research Ethics; Residencies; Resources; Risk; Role; Sampling; Scientist; Secondary to; Secure; Small Interfering RNA; Social Justice; Source; Spirometry; Stress; Techniques; Training; Translational Research; Universities; airway epithelium; anti-racism; asthmatic; asthmatic airway; bronchial epithelium; career; cell type; cohort; combinatorial; community engagement; cytokine; environmental disparity; exosome; experience; extracellular vesicles; gene environment interaction; health equity; improved; interest; knock-down; mortality; novel; patient registry; prospective; pulmonary function; racial disparity; racism; recruit; resilience; skills; stressor; success; therapy development; vesicular release

Project Summary/Abstract Although asthma is common, the morbidity/mortality rates for Black Americans are unacceptably high. Gene-by-environment interactions likely play important roles, such that greater exposures to exogenous oxidative stressors, especially unhealthy air in many US Black communities could adversely affect outcomes. These exposures also intersect with various non-biologic factors, including institutional racism. “Redlining,” or discriminatory mortgage lending and form of institutional racism, provides historic/geographically validated regions of interest across the US to study the intersection of airway biology with racial and environmental inequity. Endogenously, epithelial cells can resist exogenous oxidative stress, like air pollutants, but at the expense of reduced glutathione (GSH). In preliminary data, our lab showed that reduced GSH is depleted in epithelial cells of Type-2 Hi asthma, secondary to activation of the 15-lipoxygenase 1 (15LO1) pathway which leads to higher endogenous oxidative stress. 15LO1-Hi conditions also promote autophagy, potentially modulating the release of extracellular vesicles (EVs), including exosomes, while decreasing the release of free/’toxic” mitochondrial DNA. Unfortunately, factors that further stress epithelial cells overcome these programmed resiliency factors to induce ferroptosis, a recently identified form of cell death that promotes the release of “free” mtDNA associated with further reductions in EVs. We hypothesize that environmental hazards that increase exogenous oxidative stress, such as higher levels of exposure to air pollution as associated with racism, intersect with T2 asthma-associated, 15LO1-dependent endogenous oxidative stress in airway epithelial cells. This convergence depletes resiliency factors (GSH, “healthy” mtDNA, EVs) and increases inflammation and susceptibility to ferroptotic death, which worsens asthma outcomes. To address this hypothesis, we propose 2 aims: 1) determine the effect of increasingly toxic environments on intracellular and intercellular resiliency factors, with emphasis on the intersection with asthma biology ex vivo and 2) determine the singular and combinatorial effect of endogenous and exogenous oxidative stress on intracellular and intercellular resiliency factors in vitro. My goal is to gain cell biology, epidemiology, and bioinformatics training, facilitating my transition to an independent scientist with the necessary skill set to address the environmental health effects of racism on asthma through cutting-edge translational science. Through this fellowship, I will also receive clinical asthma, research ethics, and public health training, which will pave my path to success. The data obtained here will help me in my next career stages and also form the foundation for asthma interventions targeting communities damaged by racism.

项目概要/摘要 尽管哮喘很常见，但美国黑人的发病率/死亡率却令人难以接受 高的。基因与环境的相互作用可能发挥重要作用，因此更大的暴露 外源性氧化应激源，尤其是许多美国黑人社区的不健康空气可能会 对结果产生不利影响。这些暴露还与各种非生物因素相交叉， 包括制度性种族主义。 “红线”或歧视性抵押贷款及其形式 制度种族主义，提供了美国各地经过历史/地理验证的感兴趣区域 研究气道生物学与种族和环境不平等的交叉点。内生地， 上皮细胞可以抵抗外源性氧化应激，例如空气污染物，但代价是 还原型谷胱甘肽（GSH）。在初步数据中，我们的实验室表明还原的 GSH 在 2 型 Hi 哮喘的上皮细胞，继发于 15-脂氧合酶 1 (15LO1) 的激活 导致更高内源性氧化应激的途径。 15LO1-Hi条件也促进 自噬，可能调节细胞外囊泡（EV）的释放，包括外泌体， 同时减少游离/“有毒”线粒体 DNA 的释放。不幸的是，这些因素进一步 应激上皮细胞克服这些程序化弹性因子以诱导铁死亡，这是一种 最近发现的细胞死亡形式可促进与相关的“游离”mtDNA 的释放 进一步减少电动汽车。我们假设环境危害会增加外源性 氧化应激，例如与种族主义相关的较高水平的空气污染暴露， 与 T2 哮喘相关、15LO1 依赖性气道内源性氧化应激相交叉 上皮细胞。这种融合耗尽了弹性因素（GSH、“健康”mtDNA、EV）， 增加炎症和铁死亡的易感性，从而加重哮喘 结果。为了解决这个假设，我们提出了 2 个目标：1）确定日益增加的影响 有毒环境对细胞内和细胞间弹性因子的影响，重点是 与离体哮喘生物学的交叉，2) 确定单一和组合效应 内源性和外源性氧化应激对细胞内和细胞间弹性因子的影响 体外。我的目标是获得细胞生物学、流行病学和生物信息学培训，促进我的工作 过渡为具有解决环境问题所需技能的独立科学家 通过尖端转化科学研究种族主义对哮喘的健康影响。通过这个 奖学金期间，我还将接受临床哮喘、研究伦理和公共卫生培训，这 将为我的成功铺平道路。这里获得的数据将对我的下一个职业阶段有所帮助 也为针对受种族主义损害的社区进行哮喘干预奠定了基础。