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

项目总结/摘要 虽然哮喘是常见的，但美国黑人的发病率/死亡率是不可接受的 高基因与环境的相互作用可能发挥着重要作用， 外源性氧化应激源，特别是许多美国黑人社区的不健康空气， 对结果产生不利影响。这些接触还与各种非生物因素交叉， 包括制度性种族主义。“红线”，或歧视性抵押贷款和形式， 制度性种族主义，提供了美国各地历史/地理验证的感兴趣的地区， 研究呼吸道生物学与种族和环境不平等的交叉点。内在地， 上皮细胞可以抵抗外源性氧化应激，如空气污染物，但代价是 还原型谷胱甘肽（GSH）。在初步的数据中，我们的实验室表明，还原型GSH在 2型Hi哮喘的上皮细胞，继发于15-脂氧合酶1（15 LO 1）的激活 导致更高的内源性氧化应激的途径。15 LO 1-高条件也促进 自噬，潜在地调节细胞外囊泡（EV）的释放，包括外来体， 同时减少游离/“毒性”线粒体DNA的释放。不幸的是， 应激性上皮细胞克服这些程序性弹性因子以诱导铁凋亡， 最近发现的一种细胞死亡形式，它促进了与线粒体DNA相关的“游离”线粒体DNA的释放， 进一步减少电动汽车。我们假设，增加外源性的环境危害 氧化应激，例如与种族主义有关的空气污染程度较高， 与气道中T2哮喘相关15 LO 1依赖性内源性氧化应激交叉 上皮细胞这种融合耗尽了弹性因子（GSH，“健康”mtDNA，EV）， 增加炎症和对铁中毒死亡的易感性，这会导致哮喘 结果。为了解决这一假设，我们提出了两个目标：1）确定越来越多的影响， 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，以及2）确定 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 过渡到一个独立的科学家与必要的技能，以解决环境 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，我还将接受临床哮喘，研究伦理和公共卫生培训， 将为我的成功铺平道路在这里获得的数据将帮助我在我的下一个职业阶段， 还为针对受种族主义破坏的社区的哮喘干预措施奠定了基础。

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.