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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：
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
项目类别：
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

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