Role of the Indoor Environment on Oxidative Stress Related Sinonasal Inflammation

室内环境对氧化应激相关鼻窦炎症的作用

• 批准号: 8335447
• 负责人: Murugappan Ramanathan
• 金额: $ 24.92万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-16 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8335447
• 关键词: Adult; Air Pollution; Allergens; Allergic; Allergic rhinitis; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Attenuated; Bacteria; Basic Science; Caring; Cell Culture Techniques; Cells; Chemoprotection; Childhood Asthma; Chronic; Chronic Sinusitis; Clinical; Clinical Research; Critical Pathways; Disease; Endotoxins; Environment; Environmental Exposure; Environmental Health; Environmental Pollutants; Epithelial; Epithelial Cells; Faculty; Funding; Future; Head and Neck Surgery; Histopathology; Human; Immune; Immune response; In Vitro; Individual; Indoor Air Pollution; Inflammation; Inflammatory; Inflammatory Response; Interdisciplinary Study; K-Series Research Career Programs; Knowledge; Lead; Measures; Mediating; Medical; Mentors; Mentorship; Microbial Biofilms; Modeling; Mus; National Institute of Environmental Health Sciences; Nose; Operative Surgical Procedures; Otolaryngology; Ovalbumin; Ovum; Oxidants; Oxidative Stress; Particulate Matter; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Process; Public Health Schools; Reactive Oxygen Species; Research; Research Personnel; Resources; Role; Sinus; Sinusitis; Sulforaphane; Superantigens; Surgical Management; Testing; Therapeutic; Training; Virus; Work; airborne allergen; antimicrobial; asthmatic patient; base; biological adaptation to stress; chronic rhinosinusitis; clinical practice; cytokine; effective therapy; environmental allergen; experience; inflammatory marker; interest; medical schools; member; mouse model; novel; prevent; public health relevance; research study; rhinosinusitis; skills; transcription factor

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.

描述（由申请人提供） Murugappan Ramanathan 博士是约翰·霍普金斯大学医学院耳鼻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内科和外科治疗。他之前的研究重点是慢性鼻窦炎患者鼻窦上皮先天免疫反应受损。在该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 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来提高他的研究知识和技能，接受由经验丰富的研究人员组成的跨学科团队的直接指导，并沉浸在约翰·霍普金斯大学医学院、约翰·霍普金斯大学彭博公共卫生学院和城市环境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 博士提供成为环境暴露相关鼻窦炎症研究的独立研究者和未来领导者所需的资源。 基于之前在慢性鼻鼻腔炎症方面的研究经验，Ram​​anathan 博士现在将重点转向研究室内环境污染物和过敏原如何传播与鼻腔炎症相关的氧化应激。他还对新型药物靶向转录因子 Nrf2 如何控制粘膜炎症状态感兴趣。 在目标 1a 中，他将确定 Nrf2 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。 目标 1b 将使用在对照和慢性鼻窦炎患者的培养物中生长的鼻窦上皮细胞，并将它们在体外暴露于室内 PM 或环境小鼠过敏原。随后，将测量炎症、氧化应激和 Nrf2 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，并在鼻内小鼠过敏原激发后将鼻窦炎症水平、氧化应激和 Nrf2 调节的抗氧化剂水平关联起来。最后，在目标 2 中，Ramanathan 博士将使用萝卜硫素进行化学保护，以提高动物和细胞培养模型在环境暴露之前 Nrf2 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、课程作业和实践培训，以成为一名独立的研究者，并加深鼻腔炎症的基础科学知识。 公共卫生相关性：慢性鼻窦炎每年影响超过 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，该途径可能调节环境引起的鼻子和鼻窦炎症，并可能最终为慢性鼻窦炎带来更有效的治疗方法。