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

项目摘要 慢性鼻窦炎(CRS)是全球发病率的主要原因，其症状包括鼻塞、 流鼻水，还有分泌物。它是最常见的自我报告的慢性健康状况，并解释了 每年数十亿美元的医疗费用和损失的工作日。暴露在空气污染物中被认为是一种 CRS敏感性的临界修饰物。尽管美国的空气污染水平明显下降，但 空气污染中的细颗粒物[PM&lt；2.5(PM2.5)]和交通次生的超细污染物继续存在 在美国的许多县仍然是一个顽固的问题。PM2.5促进氧化应激和 鼻腔和鼻窦粘膜衬里的炎症导致鼻腔上皮屏障的破坏。 作为一名内科科学家，通过我的K23，我为这项提议的科学前提建立了强有力的理由 探讨依赖核相关因子-2(Nrf2)的宿主防御作为CRS修饰物的关键作用。 作为一名新的研究员，我现在正在从K23奖项过渡到独立资助的过程中。我的 初步研究表明，转录因子Nrf2参与了一系列 抗氧化和抗炎基因程序参与了上皮完整性的保存。 此外，我们的初步结果表明，长期接触PM2.5会导致Nrf2宿主不佳 可能导致CRS的防御。我们在这项提议中的中心假设是，Nrf2在 慢性阻塞性肺疾病患者上皮细胞对PM2.5的超敏反应及上皮屏障功能的调节 致CRS。我们已经组建了一个多学科的专家团队，并利用老鼠和人类提出了目标。在……里面 SA1，我们将使用一种新的CRS动物模型、Nrf2过度表达和 体内动物PM2.5暴露系统的不足和现状，以模拟与人类相关的PM2.5水平。 我们还将分析鼻窦上皮紧密连接蛋白的表达。SA2将决定 PM诱导上皮屏障功能障碍和NRF2改善通透性的机制 人鼻窦上皮细胞和新型PM2.5细胞培养暴露系统。最后，SA3将决定是否 慢性PM2.5暴露可引起鼻腔粘膜的表观遗传修饰，影响Nrf2的转录。 我们的结果将为CRS和CRS的潜在治疗靶点提供急需的翻译数据 有助于我们对这种知之甚少的疾病的了解。

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.