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

基本信息

批准号：
10684622
负责人：
Alexander James Schuyler
金额：
$ 4.43万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
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

项目摘要

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。基因与环境的相互作用可能发挥重要作用，因此暴露程度更大。外源性氧化应激，尤其是美国许多黑人社区的不健康空气可能会这些暴露也与各种非生物因素相交叉，包括制度性种族主义，即歧视性抵押贷款和形式。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。上皮细胞可以抵抗外源性氧化应激，如空气污染物，但代价是初步数据显示，还原型谷胱甘肽 (GSH) 已耗尽。 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也会促进 15LO1-Hi 条件。自噬，可能调节细胞外囊泡（EV）的释放，包括外泌体，不幸的是，同时减少了游离/“有毒”线粒体DNA的释放。应激上皮细胞克服这些程序化的弹性因子来诱导铁死亡，这是一种最近发现的细胞死亡形式可以促进与相关的“游离”mtDNA 的释放我们捕捉到了增加外源性的环境危害。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这种融合会消耗弹性因子（GSH、“健康”mtDNA、EV）并增加炎症和铁死亡的易感性，从而加重哮喘为了解决这一假设，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我的目标是获得细胞生物学、流行病学和生物信息学培训，以促进我的工作。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。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，在这里获得的数据将为我的下一个职业阶段提供帮助。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。