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: 10077827
• 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/10077827
• 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; Structure; 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 慢性鼻塞炎（CRS）是全球发病率的主要原因，鼻塞等症状， Rhinorrhea和排出。它是最常见的自我报告的慢性健康状况，并说明 数十亿美元的医疗保健费用和每年损失的工作日。暴露于空气污染物被认为是 CRS敏感性的关键修饰符。尽管美国的空气污染水平明显降低，但 空气污染的细胞颗粒成分[PM <2.5（PM2.5）]和继发于交通的超细污染物继续 在美国许多县仍然是一个顽固问题。 PM2.5促进氧化应激和 鼻子和鼻窦的粘膜衬里的炎症，导致鼻窦上皮屏障破坏。 作为一个身体科学家，通过我的K23，我为该提案的科学前提开发了一个强大的理由 研究核相关因子2（NRF2）依赖宿主防御的关键作用，作为CRS的修饰符。 作为新的调查员，我现在正在从K23奖项过渡到独立资金。我的 初步研究表明，转录因子NRF2参与了一系列阵列的上调 抗氧化剂和抗炎基因程序涉及上皮完整性。 此外，我们的初步结果表明，慢性PM2.5暴露会导致次优的NRF2主机 可能导致CRS的防御。我们在此提案中的核心假设是NRF2在 对PM2.5的上皮细胞超敏反应和领先患者上皮屏障功能的调节 到CRS。我们已经组建了一个由小鼠和人类组成的专家组成的多学科团队。在 SA1，我们将使用新的CRS动物模型，NRF2过表达的模型和 艺术的缺乏和状态体内动物PM2.5暴露于与人类相关的模仿PM2.5的水平。 我们还将分析鼻纳纳斯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和NRF2的机制可以使用这种渗透性来改善这种渗透性 人鼻窦上皮细胞和新型的PM2.5细胞培养暴露系统。最后，sa3将确定是否 慢性PM2.5暴露会导致影响NRF2转录的鼻窦粘膜表观遗传修饰。 我们的结果将提供急需的翻译数据，以靶向CRS中的潜在治疗目标 有助于我们对这种不良理解的疾病的了解。