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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

基本信息

批准号：
10532380
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-04 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10532380
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 County Critical Pathways Cytoskeleton Data Disease Down-Regulation Enhancers Environmental Exposure Epigenetic Process Epithelial Cells Epithelium Exposure to Functional disorder Funding Genes Genetic Transcription Genomics Health Health Care Costs Host Defense Human Hypersensitivity Inflammation Link Liquid substance Measurement Mediating Medical Mentored Patient-Oriented Research Career Development Award Methylation 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 chronic rhinosinusitis clinically relevant effective therapy epigenome epigenomics fine particles in vivo innovation mouse model multidisciplinary novel overexpression pollutant preservation prevent programs promoter rhinosinusitis rho small molecule symptom treatment transcription factor transcriptome

项目摘要

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、鼻漏、分泌物。它是最常见的自我报告的慢性健康状况，占每年造成数十亿美元的医疗费用和工作日损失。接触空气污染物被认为是 CRS 易感性的关键调节因子。尽管美国的空气污染水平显着下降，空气污染的细颗粒物成分[PM <2.5  (PM2.5)]和交通继发的超细污染物继续在美国许多县仍然是一个顽固的问题。 PM2.5 促进氧化应激鼻子和鼻窦粘膜内层炎症导致鼻窦上皮屏障破坏。作为一名医师科学家，通过我的 K23，我为该提案的科学前提提出了强有力的理由研究核相关因子 2 (Nrf2) 依赖性宿主防御作为 CRS 修饰剂的关键作用。作为一名新研究者，我现在正处于从 K23 资助过渡到独立资助的过程中。我的初步研究表明转录因子 Nrf2 参与一系列的上调参与保护上皮完整性的抗氧化和抗炎基因程序。此外，我们的初步结果表明，长期接触 PM2.5 会导致 Nrf2 宿主不理想可能导致 CRS 的防御。我们在这个提案中的中心假设是 Nrf2 在上皮细胞对 PM2.5 过敏和上皮屏障功能的调节导致患者到 CRS。我们组建了一个多学科专家团队，并提出了利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 过度表达模型和动物体内 PM2.5 暴露系统的缺陷和最先进的水平，以模拟与人类相关的 PM2.5 水平。我们还将分析鼻腔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 通过使用改善这种通透性人鼻窦上皮细胞和新型 PM2.5 细胞培养物暴露系统。最后，SA3 将确定是否长期接触 PM2.5 会导致鼻窦粘膜发生表观遗传修饰，影响 Nrf2 转录。我们的结果将为 CRS 和 CRS 的潜在治疗目标提供急需的转化数据有助于我们了解这种知之甚少的疾病。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Exposure to Particulate Matter Air Pollution and Anosmia.

DOI：
10.1001/jamanetworkopen.2021.11606
发表时间：
2021-05-03
期刊：
JAMA network open
影响因子：
13.8
作者：
Zhang Z;Rowan NR;Pinto JM;London NR;Lane AP;Biswal S;Ramanathan M Jr
通讯作者：
Ramanathan M Jr

Long-term ambient air pollution exposure and risk of sinonasal inverted papilloma.

DOI：
10.1002/alr.22968
发表时间：
2022-09
期刊：
INTERNATIONAL FORUM OF ALLERGY & RHINOLOGY
影响因子：
6.4
作者：
Mydlarz, Wojciech K.;London, Nyall R.;Biswal, Shyam;Ramanathan, Murugappan;Zhang, Zhenyu
通讯作者：
Zhang, Zhenyu

Role of Environmental Air Pollution in Chronic Rhinosinusitis.

DOI：
10.1007/s11882-021-01019-6
发表时间：
2021-09-09
期刊：
Current allergy and asthma reports
影响因子：
5.5
作者：
Leland EM;Zhang Z;Kelly KM;Ramanathan M Jr
通讯作者：
Ramanathan M Jr

Environmental air pollution and chronic rhinosinusitis: A systematic review.

DOI：
10.1002/lio2.774
发表时间：
2022-04
期刊：
LARYNGOSCOPE INVESTIGATIVE OTOLARYNGOLOGY
影响因子：
1.9
作者：
Leland, Evelyn M.;Vohra, Varun;Seal, Stella M.;Zhang, Zhenyu;Ramanathan, Murugappan, Jr.
通讯作者：
Ramanathan, Murugappan, Jr.

Particulate matter air pollution exposure disrupts the Nrf2 pathway in sinonasal epithelium via epigenetic alterations in a murine model.

DOI：
10.1002/alr.23010
发表时间：
2022-11
期刊：
International forum of allergy & rhinology
影响因子：
6.4
作者：
Park B;London NR Jr;Tharakan A;Rengasamy P;Rajagopalan S;Biswal S;Pinto JM;Ramanathan M Jr
通讯作者：
Ramanathan M Jr