Role of the Indoor Environment on Oxidative Stress Related Sinonasal Inflammation

描述(由申请人提供) Murugappan Ramanathan博士是约翰·霍普金斯医学院耳鼻咽喉头颈外科的初级教员，他的临床实践致力于鼻和鼻窦疾病的内科和外科管理。他之前的研究重点是慢性鼻窦炎患者鼻窦上皮天然免疫反应受损。在这项导师职业发展奖的支持下，Ramanathan博士试图更好地了解室内环境暴露(颗粒物和过敏原)对Nrf2抗氧化途径调节的基于氧化应激的鼻窦炎症的影响。Ramanathan博士将通过环境健康和空气污染方面的课程工作来增强他的研究知识和技能，接受一个由经验丰富的研究人员组成的跨学科团队的指导，并沉浸在约翰霍普金斯大学医学院、约翰霍普金斯大学布隆伯格公共卫生学院和城市环境中儿童哮喘中心的跨学科研究和临床环境中。这一职业发展奖将为Ramanathan博士提供所需的资源，使他成为与环境暴露相关的鼻鼻炎研究的独立研究员和未来的领导者。 基于他以前在慢性鼻窦炎方面的研究经验，Ramanathan博士现在将他的重点转移到研究室内环境污染物和过敏原如何传播氧化应激相关的鼻鼻炎上。他还对新药靶向转录因子Nrf2如何控制粘膜炎症状态感兴趣。在目标1a中，他将在过敏性鼻炎小鼠模型中确定Nrf2在调节室内颗粒物(PM)诱导的鼻窦炎中的作用。目的1b将使用培养自对照组和慢性鼻窦炎患者的鼻窦上皮细胞，并在体外将它们暴露于室内PM或环境中的小鼠变应原。随后，将测量炎症、氧化应激和依赖Nrf2的抗氧化剂的水平。在目标1c中，Ramanathan博士将使用现有NIEHS哮喘饮食研究中的哮喘患者，并将鼻腔炎症水平、氧化应激水平以及小鼠鼻内过敏原攻击后Nrf2调节的抗氧化剂水平联系起来。最后，在目标2中，Ramanathan博士将使用萝卜硫素进行化学保护，以在环境暴露之前提高动物和细胞培养模型中Nrf2调节的抗氧化剂的水平。进行这些实验的过程将为候选人提供必要的指导、课程安排和实践培训，使其成为一名独立的研究人员，并进一步了解鼻窦炎症的基本科学知识。 公共卫生相关性：慢性鼻-鼻窦炎每年困扰3000多万人，是美国患者寻求医疗护理的最常见疾病之一。虽然这种疾病的发病机制是多因素的，但很少有研究检查环境暴露的作用。这项建议将研究一条关键途径的作用，该途径可能调节环境引起的鼻和鼻窦炎症，并最终可能导致对慢性鼻窦炎的更有效的治疗。

DESCRIPTION (provided by applicant) Dr. Murugappan Ramanathan is a junior faculty member in the Department of Otolaryngology-Head & Neck Surgery at the Johns Hopkins School of Medicine where his clinical practice is dedicated to the medical and surgical management of nasal and sinus disorders. His previous research focused on impaired sinonasal epithelial innate immune responses in patients with chronic sinusitis. With the support of this Mentored Career Development Award, Dr. Ramanathan seeks to better understand the impact of indoor environmental exposure (particulate matter and allergens) on oxidative stress based sinonasal inflammation regulated by the Nrf2 anti- oxidant pathway. Dr. Ramanathan will enhance his research knowledge and skills with coursework in environmental health and air pollution, receive directed mentorship by an interdisciplinary team of experienced researchers, and be immersed in the interdisciplinary research and clinical environments of the Johns Hopkins School of Medicine, Johns Hopkins Bloomberg School of Public Health, and the Center for Childhood Asthma in the Urban Environment. This Career Development Award will provide Dr. Ramanathan with the resources that he needs to become an independent investigator and future leader in environmental exposure related sinonasal inflammation research. Building on his prior research experience in chronic sinonasal inflammation, Dr. Ramanathan has now transitioned his focus towards examining how the indoor environmental pollutants and allergens propagate oxidative stress related sinonasal inflammation. He is also interested in how the novel drug targetable transcription factor, Nrf2, may control the mucosal inflammatory state. In Aim 1a, he will determine the role of Nrf2 in regulating indoor particulate matter (PM) induced sinonasal inflammation in an allergic rhinitis mouse model. Aim 1b will use sinonasal epithelial cells grown in culture from control and chronic sinusitis patients and expose them in vitro to indoor PM or environmental mouse allergen. Subsequently, levels of inflammation, oxidative stress, and Nrf2 dependent antioxidants will be measured. In Aim 1c, Dr. Ramanathan will use asthmatic patients from the existing NIEHS ASTHMA-DIET study and correlate sinonasal levels of inflammation, oxidative stress, and levels of Nrf2 regulated antioxidants after intranasal mouse allergen challenge. Finally, in Aim 2, Dr. Ramanathan will use sulforaphane for chemoprotection to enhance levels of Nrf2 regulated antioxidants in both animal and cell culture models prior to environmental exposures. The process of performing these experiments will provide the candidate with the necessary guidance, coursework, and practical training towards becoming an independent investigator as well as furthering the basic science knowledge of sinonasal inflammation. Public Health Relevance: Chronic rhinosinusitis afflicts greater than 30 million individuals yearly and is among the most common conditions for which patients seek medical care in the US. While the pathogenesis of this disease is multi-factorial, very little research has examined the role of environmental exposure. This proposal will study the role of a critical pathway that may regulate environmentally induced inflammation in the nose and sinus and may ultimately lead to more effective therapies for chronic sinusitis.