The Role of Nrf2 in Stabilizing the Epithelial Barrier in Particulate Matter Induced Rhinosinusitis

Nrf2 在稳定颗粒物诱发鼻窦炎的上皮屏障中的作用

• 批准号: 10320369
• 负责人: Murugappan Ramanathan
• 金额: $ 40.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-04 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320369
• 关键词: Actins; Adherens Junction; Affect; Air; Air Pollutants; Air Pollution; American; Animal Model; Animals; Anti-Inflammatory Agents; Antioxidants; Biological Assay; Caring; Cell Culture Techniques; Chronic; Complement; Congestive; County; Critical Pathways; Cytoskeleton; Data; Disease; Down-Regulation; Enhancers; Environmental Exposure; Epigenetic Process; Epithelial; Epithelial Cells; Exposure to; Functional disorder; Funding; Genes; Genetic Transcription; Genomics; Health; Health Care Costs; Host Defense; Human; Hypersensitivity; Inflammation; Lead; Link; Liquid substance; Measurement; Mediating; Medical; Mentored Patient-Oriented Research Career Development Award; Modeling; Modification; Molecular; Morbidity - disease rate; Mucous Membrane; Mus; Myosin ATPase; Myosin Light Chain Kinase; Nose; Nuclear; Oxidative Stress; Particulate; Particulate Matter; Pathogenesis; Patient Self-Report; Patients; Permeability; Physicians; Play; Predisposition; Process; Proteins; Protocols documentation; Reactive Oxygen Species; Regulation; Research Personnel; Rho-associated kinase; Role; Scientist; Secondary to; Signal Pathway; Sinus; Site; Symptoms; System; Testing; Tight Junctions; Ultrafine; United States; Up-Regulation; Work; aerosolized; base; chronic rhinosinusitis; clinically relevant; effective therapy; epigenome; epigenomics; in vivo; innovation; mouse model; multidisciplinary; novel; overexpression; pollutant; preservation; prevent; programs; promoter; rhinosinusitis; rho; small molecule; symptom treatment; transcription factor; transcriptome

Project Abstract Chronic Rhinosinusitis (CRS) is a leading cause of morbidity globally with symptoms such as nasal congestion, rhinorrhea, and discharge. It is the single most common self-reported chronic health condition and accounts for billions of dollars in health care costs and lost work days annually. Exposure to air pollutants is thought to be a critical modifier of CRS susceptibility. Despite marked reductions in air pollution levels in the United States, the fine particulate component of air pollution [PM <2.5  (PM2.5)] and ultrafine pollutants secondary to traffic continue to remain a recalcitrant issue in many counties in the United States. PM2.5 promotes oxidative stress and inflammation in the mucosal lining of the nose and sinuses contributing to sinonasal epithelial barrier disruption. As a physician-scientist, through my K23, I developed a strong rationale for the scientific premise of this proposal to investigate the critical role of Nuclear related factor-2 (Nrf2) dependent host defense as a modifier of CRS. As a new investigator, I am now in the process of transitioning from a K23 award to independent funding. My preliminary studies have indicated that the transcription factor, Nrf2 is involved in the upregulation of an array of anti-oxidant and anti-inflammatory gene programs involved in the preservation of epithelial integrity. Furthermore, our preliminary results have indicated that chronic PM2.5 exposure causes suboptimal Nrf2 host defense that may lead to CRS. Our central hypothesis in this proposal is that Nrf2 plays a critical role in epithelial cell hypersensitivity to PM2.5 and modulation of epithelial barrier function in patients leading to CRS. We have assembled a multidisciplinary team of experts and propose aims using mice and humans. In SA1, we will test this hypothesis using a novel animal model of CRS, models of Nrf2 over-expression and deficiency and state of the art in-vivo animal PM2.5 exposure system to mimic levels of PM2.5 relevant to humans. We will also analyze expression of sinonasal epithelial tight junctional proteins. SA2 will determine the mechanism by which PM induces epithelial barrier dysfunction and Nrf2 ameliorates this permeability using human sinonasal epithelial cells and a novel PM2.5 cell culture exposure system. Lastly, SA3 will determine if chronic PM2.5 exposure can cause epigenetic modifications in the sinonasal mucosa affecting Nrf2 transcription. Our results will provide much needed translational data to target potential treatment targets in CRS and contribute to our knowledge of this poorly understood disorder.

项目摘要 慢性鼻窦炎（CRS）是全球发病的主要原因，其症状包括鼻塞， 阴道分泌物和分泌物。它是最常见的自我报告的慢性健康状况， 每年数十亿美元的医疗费用和损失的工作日。暴露于空气污染物被认为是一种 CRS敏感性的关键修改器。尽管美国的空气污染水平显著下降， 空气污染的细颗粒物成分[PM <2.5 μ m（PM2.5）]和交通二次污染的超细污染物继续存在 在美国的许多县仍然是一个棘手的问题。PM2.5促进氧化应激， 鼻和鼻窦粘膜内层的炎症导致鼻窦上皮屏障破坏。 作为一名物理学家兼科学家，通过我的K23，我为这个提议的科学前提建立了一个强有力的理论基础 研究核相关因子2（Nrf2）依赖的宿主防御作为CRS修饰剂的关键作用。 作为一名新的调查员，我现在正在从K23奖过渡到独立资助。我 初步研究表明，转录因子Nrf2参与了一系列转录因子的上调。 参与上皮完整性保护的抗氧化和抗炎基因程序。 此外，我们的初步结果表明，慢性PM2.5暴露导致次优Nrf2宿主 可能导致CRS的防御。我们在这个提议中的中心假设是Nrf2在以下方面起着关键作用： 上皮细胞对PM2.5的超敏反应和导致患者上皮屏障功能的调节 CRS的。我们已经组建了一个多学科的专家团队，并提出了使用小鼠和人类的目标。在 SA1，我们将使用一种新的CRS动物模型、Nrf2过表达模型和 缺乏和现有技术水平的体内动物PM2.5暴露系统来模拟与人类相关的PM2.5水平。 我们也将分析鼻窦上皮紧密连接蛋白的表达。SA2将确定 PM诱导上皮屏障功能障碍的机制，Nrf2使用 人鼻窦上皮细胞和一种新的PM2.5细胞培养暴露系统。最后，SA3将确定是否 慢性PM2.5暴露可引起影响Nrf2转录的鼻窦粘膜中的表观遗传修饰。 我们的研究结果将提供急需的翻译数据，以靶向CRS中的潜在治疗靶点， 有助于我们对这种知之甚少的疾病的了解。