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.

项目摘要/摘要 尽管哮喘很常见，但黑人美国人的发病率/死亡率是不可接受的 高的。逐个环境的相互作用可能起着重要的作用，从而更大的暴露 出现外源氧化压力源，尤其是许多美国黑人社区的不健康空气 不利影响结果。这些暴露也与各种非生物因素相交， 包括制度种族主义。 “红线”，或歧视性抵押贷款和形式 机构种族主义，为美国提供历史性/地理验证的感兴趣地区 研究气道生物学与种族和环境不平等的交集。内在， 上皮细胞可以抵抗外源氧化物应激，例如空气污染物，但以牺牲为代价 减少谷胱甘肽（GSH）。在初步数据中，我们的实验室表明，减少的GSH耗尽 2型HI哮喘的上皮细胞，继发于15-脂氧合酶1的激活（15LO1） 导致较高内源性氧化应激的途径。 15lo1-Hi条件也促进 自噬，可能调节细胞外蔬菜（EV）的释放，包括外泌体， 虽然减少了自由/'毒性”线粒体DNA的释放。不幸的是，进一步的因素 压力上皮细胞克服了这些编程的弹性因子以诱导铁铁作用，A 最近确定的细胞死亡形式，促进了与 电动汽车的进一步减少。我们假设会增加外源性的环境危害 氧化应激，例如与种族主义相关的空气污染的较高水平， 与T2哮喘相关的15lo1依赖性内源性氧化应激相交 上皮细胞。这种收敛耗尽了弹性因子（GSH，“健康” mtDNA，EVS）和 增加影响力和对铁毒性死亡的易感性，这使哮喘恶化 结果。为了解决这一假设，我们提出了2个目标：1）确定越来越多的效果 在细胞内和细胞间弹性因素上有毒环境，重点是 与哮喘生物学的交点是体内和2）确定的奇异和组合效应 内源性和外源性氧化应激对细胞内和细胞间弹性因子的氧化应激 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 过渡到独立科学家，具有必要的技能来解决环境 种族主义通过尖端转化科学对哮喘的健康影响。通过这个 奖学金，我还将接受临床哮喘，研究伦理和公共卫生培训，这 将铺平我的成功之路。这里获得的数据将在我的下一个职业阶段对我有所帮助， 还构成了针对种族主义损害社区的哮喘干预措施的基础。