Role of the Indoor Environment on Oxidative Stress Related Sinonasal Inflammation

描述（由申请人提供） 博士Murugappan Ramanathan是约翰霍普金斯医学院耳鼻咽喉头颈外科系的初级教员，他的临床实践致力于鼻和鼻窦疾病的医疗和手术管理。他以前的研究主要集中在慢性鼻窦炎患者的鼻窦上皮先天免疫反应受损。在这个指导职业发展奖的支持下，Ramanathan博士寻求更好地了解室内环境暴露（颗粒物和过敏原）对由Nrf 2抗氧化途径调节的基于氧化应激的鼻窦炎症的影响。 Ramanathan博士将通过环境卫生和空气污染课程提高他的研究知识和技能，接受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医学院，约翰霍普金斯彭博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。该职业发展奖将为Ramanathan博士提供他成为环境暴露相关鼻窦炎研究的独立研究者和未来领导者所需的资源。 基于他之前在慢性鼻窦炎方面的研究经验，Ramanathan博士现在将重点转移到研究室内环境污染物和过敏原如何传播与氧化应激相关的鼻窦炎。他还对新型药物靶向转录因子Nrf 2如何控制粘膜炎症状态感兴趣。 在目标1a中，他将确定Nrf 2在调节过敏性鼻炎小鼠模型中室内颗粒物（PM）诱导的鼻窦炎症中的作用。 目的1b将使用对照组和慢性鼻窦炎患者培养的鼻窦上皮细胞，并将其体外暴露于室内PM或环境小鼠变应原。随后，将测量炎症、氧化应激和Nrf 2依赖性抗氧化剂的水平。 在目标1c中，Ramanathan博士将使用现有NIEHS ASTHMA-DIET研究中的哮喘患者，并将鼻内小鼠过敏原激发后的炎症，氧化应激和Nrf 2调节的抗氧化剂水平与鼻窦水平相关联。最后，在目标2中，Ramanathan博士将使用萝卜硫素进行化学保护，以提高环境暴露前动物和细胞培养模型中Nrf 2调节的抗氧化剂水平。进行这些实验的过程将为候选人提供必要的指导，课程和实践培训，以成为独立的研究者，并进一步提高鼻窦炎症的基础科学知识。 公共卫生相关性：慢性鼻窦炎每年折磨超过3000万人，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，但很少有研究探讨环境暴露的作用。该提案将研究一个关键途径的作用，该途径可能调节鼻和鼻窦中环境诱导的炎症，并可能最终导致更有效的慢性鼻窦炎治疗。

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.