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篇摘要 2 3、引起哮喘加重。研究报告称， 4妇女比男子多，但这些差异背后的机制仍不清楚。虽然女性 5肺，与男性肺相比，暴露于增加的雌激素和孕酮水平， 6生理和环境来源，目前尚不清楚是否结合性激素和臭氧 7、影响肺部健康。在这种情况下，高水平的臭氧和女性是负面的预后 慢性呼吸道疾病发病率和死亡率增加的8项指标。 9本K 01提案的总体目标是为 10候选人，而她研究臭氧引起的男性和女性肺部炎症的机制。 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研究她以前曾从事各种各样的研究项目，从内分泌学和 13生物化学免疫学和肺生理学，她已经证明了生产力和潜力， 14独立她的长期职业目标是发展成为一个独立和富有成效的科学家， 15以创造性和科学严谨的方法调查肺部疾病相关研究。通过 16综合的方法，本项目将促进候选人的科学和职业发展与指导 17名来自资深和经验丰富的导师，一个由各方面专家组成的科学咨询委员会 18拟议的工作，并额外的学术和实践培训，以获得新的研究专业知识。的 宾夕法尼亚州立大学医学院提供了一个独特的环境，以促进成功的 20名候选人，包括财政承诺和研究时间的保护，具有专业知识的高级教师， 21个研究领域，一个合作和培育环境，并获得专门的资源，设备， 22、完成项目所需的设施。候选人是一个部门的教员， 23儿科和生物化学和分子生物学，在那里她可以获得该领域的专业知识 来自不同背景的基础和临床研究者的24项肺病研究。 [25]拟议研究计划的中心假设是，男性和女性的性激素都可以 26调节臭氧引起的肺部炎症反应。通过多学科方法， 27提案将通过以下目的来检验这一假设：1）表征肺功能的性别差异， 28炎症对臭氧暴露的反应，2）确定性激素在臭氧诱导的肺中的作用 评价臭氧和性激素在哮喘炎症中的作用。虽然 30先前的临床研究已经表明激素状态可以影响女性哮喘恶化， 这是第一个研究男性和女性性激素在臭氧诱导的 32正常和哮喘小鼠肺部的炎症。这些拟议的研究将共同促进 33科学发展的候选人，增加对性激素的作用的认识 34对主要空气污染物的炎症反应。由于预计环境臭氧水平将随着气候变化而上升， 35变化，臭氧相关的哮喘急诊室访问预计将增加。因此，改进的 了解性激素在哮喘炎症发病中的作用具有较高的临床价值 37的意义，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，