Sex-specific mechanisms of ozone-induced acute lung inflammation

臭氧引起的急性肺部炎症的性别特异性机制

• 批准号: 9316707
• 负责人: Patricia Silveyra
• 金额: $ 15.04万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9316707
• 关键词: Acute; Advisory Committees; Affect; Air Pollutants; Air Pollution; Allergic Reaction; Area; Asthma; Basic Science; Biochemistry; Breathing; Cells; Chronic; Climate; Clinical; Clinical Investigator; Clinical Research; Data; Development; Disease; Dose; Emergency department visit; Endocrinology; Environment; Equipment; Estradiol; Estrogens; Estrous Cycle; Event; Exposure to; Faculty; Female; Flow Cytometry; Foundations; Gender; Gender Role; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Generations; Genes; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Health; High Prevalence; Hormonal; Hormones; Hospitalization; Immune response; Immunology; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Knowledge; Laboratories; Lead; Lung; Lung Inflammation; Lung diseases; Mediating; Medicine; Men' s Role; Mentors; Methodology; Modeling; Molecular; Molecular Biology; Morbidity - disease rate; Mus; Outcome; Ozone; Pathogenesis; Pathway interactions; Patients; Pediatrics; Pennsylvania; Physiological; Physiology; Process; Productivity; Progesterone; Reporting; Research; Research Project Grants; Resources; Respiratory physiology; Risk; Rodent; Role; Scientist; Severities; Sex Characteristics; Signal Pathway; Site; Source; Structure; Testing; Testosterone; Time; Training; Universities; Ventilator; Woman; Women' s Role; Work; airway inflammation; ambient air pollution; asthmatic; cardiovascular injury; career; career development; college; experience; improved; inflammatory lung disease; interdisciplinary approach; male; member; men; mortality; novel; ozone exposure; perimenstrual; prevent; prognostic; respiratory; response; senior faculty; sex; success; therapeutic target; transcription factor; tropospheric ozone

1 ABSTRACT 2 3 and cause asthma exacerbations. Studies have reported a higher prevalence of inflammatory lung disease in 4 women than men, but the mechanisms underlying these disparities are still unknown. Although the female 5 lung, as compared to the male lung, is exposed to increased levels of estrogen and progesterone from both 6 physiological and environmental sources, it is not known whether the combination of sex hormones and ozone 7 can affect lung health. In this context, high levels of ozone and female gender are negative prognostic 8 indicators for increased morbidity and mortality from chronic respiratory disease. 9 The overall objectives of this K01 proposal are to provide additional training and laboratory expertise to the 10 candidate, while she investigates mechanisms of ozone-induced inflammation in the male and female lung. 11 The candidate is a well-qualified junior scientist with a strong track record of commitment to academic 12 research. She has previously engaged in a wide variety of research projects, ranging from endocrinology and 13 biochemistry to immunology and lung physiology, and she has demonstrated productivity and potential for 14 independence. Her long term career goal is to develop into an independent and productive scientist who 15 investigates lung disease-relevant research with a creative and scientifically rigorous methodology. Through an 16 integrated approach, this project will promote the candidate's scientific and career development with guidance 17 from senior and experienced mentors, a scientific advisory committee comprised of experts in various aspects 18 of the proposed work, and additional academic and hands-on training to acquire new research expertise. The 19 Pennsylvania State University College of Medicine offers a unique environment to promote the success of the 20 candidate, including a financial commitment and protection of research time, senior faculty with expertise in the 21 research area, a collaborative and nurturing environment, and access to specialized resources, equipment, 22 and facilities necessary to complete the project. The candidate is a faculty member of the Departments of 23 Pediatrics and Biochemistry and Molecular Biology, where she has access to specialized expertise in the areas 24 of lung disease research from basic and clinical investigators of diverse backgrounds. 25 The central hypothesis of the proposed research plan is that both male and female sex hormones can 26 modulate ozone-induced inflammatory responses in the lung. Through a multidisciplinary approach, this 27 proposal will test this hypothesis via the following aims: 1) to characterize sex differences in lung function and 28 inflammation in response to ozone exposure, 2) to determine the role of sex hormones in ozone-induced lung 29 inflammation, and 3) to evaluate the effects of ozone and sex hormones in asthmatic inflammation. Although 30 previous clinical studies have indicated that the hormonal status can affect asthma exacerbations in women, 31 this is the first study to examine the specific roles of male and female sex hormones in ozone-induced 32 inflammation in the lungs of both normal and asthmatic mice. Together, the proposed studies will promote the 33 scientific development of the candidate and increase the understanding of the role of sex hormones in the 34 inflammatory response to a major air pollutant. As ambient ozone levels are anticipated to rise with climate 35 change, ozone-related asthma emergency room visits are expected to increase. Therefore, an improved 36 understanding of the role of sex hormones in the pathogenesis of asthmatic inflammation is of high clinical 37 significance, and will open the door for discovery of new gender specific therapeutic targets. 38 Ozone is a major component of urban air pollution known to affect lung function, increase airway inflammation,

1 摘要 2 3、引起哮喘发作。研究表明，炎症性肺病的患病率较高 4 女性比男性多，但造成这些差异的机制仍不清楚。虽然是女的 5 与男性肺相比，肺暴露于雌激素和黄体酮水平升高的情况下 6 生理环境来源，尚不清楚性激素与臭氧是否结合 7.会影响肺部健康。在这种情况下，高水平的臭氧和女性性别是负面的预后 慢性呼吸道疾病发病率和死亡率增加的 8 项指标。 9 该 K01 提案的总体目标是为 10 号候选人，同时她研​​究臭氧引起的男性和女性肺部炎症的机制。 11 候选人是一位合格的初级科学家，具有良好的学术承诺记录 12 研究。她之前从事过各种研究项目，从内分泌学到 13 生物化学到免疫学和肺生理学，她已经展示了生产力和潜力 14 独立性。她的长期职业目标是发展成为一名独立且多产的科学家 15 采用创造性且科学严谨的方法来调查与肺部疾病相关的研究。通过一个 16个综合方法，该项目将为候选人的科学和职业发展提供指导 17名资深、经验丰富的导师，由各方面专家组成的科学顾问委员会 18 项拟议工作，以及额外的学术和实践培训，以获得新的研究专业知识。这 19 宾夕法尼亚州立大学医学院提供了一个独特的环境来促进研究的成功 20 名候选人，包括财务承诺和研究时间保护，具有该领域专业知识的高级教师 21个研究领域、协作和培育环境以及获得专业资源、设备、 22 以及完成该项目所需的设施。候选人是以下院系的教员 23 儿科、生物化学和分子生物学，她可以获得这些领域的专业知识 24 来自不同背景的基础和临床研究人员的肺部疾病研究。 25 拟议研究计划的中心假设是男性和女性性激素都可以 26 调节臭氧引起的肺部炎症反应。通过多学科方法，这 27 提案将通过以下目标检验这一假设：1）描述肺功能的性别差异和 28 臭氧暴露反应的炎症，2) 确定性激素在臭氧引起的肺中的作用 29 炎症，3) 评估臭氧和性激素对哮喘炎症的影响。虽然 此前的 30 项临床研究表明，荷尔蒙状态会影响女性哮喘发作， 31 这是第一项研究男性和女性性激素在臭氧引起的 32 正常小鼠和哮喘小鼠的肺部炎症。总之，拟议的研究将促进 33 科学发展候选人并增加对性激素在性激素中作用的理解 34 对主要空气污染物的炎症反应。由于环境臭氧水平预计会随着气候变化而上升 35日变化，臭氧相关哮喘急诊室就诊人数预计将增加。因此，改进的 36 了解性激素在哮喘炎症发病机制中的作用具有较高的临床意义 37 意义重大，并将为发现新的性别特异性治疗靶点打开大门。 38 臭氧是城市空气污染的主要成分，已知会影响肺功能，增加气道炎症，