The role of omega-3 fatty acids and bioactive lipid signaling in airway inflammation and resolution following organic dust exposures

 描述（由申请人提供） 在农业行业，有机粉尘暴露会引发有害的气道炎症，从事集中动物饲养作业的个人会患上与工作有关的炎症性肺病，包括慢性支气管炎和阻塞性气道疾病。现有的治疗方法不能充分治疗所产生的气道疾病。因此，迫切需要新的预防或治疗方案来对抗这些暴露的有害炎症作用。富含ω-3脂肪酸（ω-3 FA）的饮食对健康的益处是公认的，但尚未完全了解。最近的研究表明，某些ω-3 FA衍生物积极地减弱和解决炎症过程;这些专门的促消退介质（SPM）可能是ω-3 FA有益作用的关键。在治疗策略中利用ω-3 FA和SPM的保护特性可以彻底改变我们对抗衰弱性气道疾病的方式。然而，还没有完全了解ω-3 FA和SPM如何在肺中发挥作用以限制炎症并促进消退。因此，本研究的目的是确定ω-3 FA及其SPM衍生物在调节有机粉尘诱导的气道炎症中的作用。据推测，ω-3 FA及其SPM衍生物调节暴露于农业粉尘后气道炎症的主动消退。为了检验这一假设，提出了三个具体目标。目的1的重点是描述补充ω-3 FA对减轻有机粉尘诱导的急性和慢性气道炎症的体内作用。目的2探讨ω-3 FA对有机粉尘刺激的BEC的抗炎促分解作用机制。目的2a将确定环氧合酶和脂氧合酶酶途径在调节由DE刺激的补充二十二碳六烯酸（DHA）的支气管上皮细胞中脂质介质产生中的作用。目的2b将定义DHA治疗如何改变DE刺激的BEC中TAK 1介导的炎症信号传导。本申请的目的3研究ω-3 FA如何调节慢性有机粉尘诱导的T细胞和巨噬细胞活化。这些研究有望通过证明ω-3 FA如何积极调节肺部炎症消退而产生重要的积极影响。这些结果将揭示涉及ω-3 FA补充的干预措施在预防和治疗广泛的炎性气道疾病中的潜力。 除了上述提出的研究目标的性能之外，本申请的主要目标是提供生物活性脂质领域的培训，以帮助候选人从博士后研究员成功过渡到独立研究员。 她的长期职业目标是成为学术界一名成功的独立研究员。 候选人计划制定一个富有成效的研究计划，增加深度和活力，以环境健康研究领域的重点是免疫和疾病预防和缓解的自然，内源性手段。她的NIEHS-F32提供了环境健康和呼吸毒理学方面的培训，而K99将使她能够发展生物活性脂质信号传导和代谢方面的专业知识，包括学习对她在该领域取得成功至关重要的新技术。 候选人的学术研究环境非常适合为她提供本申请中提出的必要培训。内布拉斯加大学医学中心的肺部研究小组有六个NIH，三个CDC和两个VA资助的基础研究项目，与候选人提出的研究培训和调查领域有关。学术校园的协作性质允许每天与基础科学家，临床医生和其他学员频繁接触。达勒姆研究中心II建于2009年，包括最先进的研究核心设施和完整的动物设施，具有执行提案中描述的所有先进技术的能力。 候选人提出的职业发展活动旨在加强她在生物活性脂质研究领域的知识和经验，并提高她的实验室管理和监督技能。在我的K99阶段，候选人将直接与哈佛医学院的布鲁斯利维博士合作，学习如何制备和处理液相色谱-质谱技术的样品，并分析脂质代谢产物谱的输出。她将参加杰克逊实验室的“整个科学家”为期4天的研讨会，以加强她在指导，沟通，实验室管理和创业方面的技能和经验。她将参加ATS研究生课程，“使用`组学研究肺部疾病”，以提高她从我的研究中使用的体内模型和其他模型中获得可靠、有意义的机制数据的能力。 候选人计划参加第15届类花生酸研究基金会的国际会议上生物活性脂质在癌症炎症和相关疾病，除了年度ATS会议。她还将参加提供的相关Keystone研讨会，即脂质代谢系统生物学研讨会和/或基于相关性的年度克恩脂质会议。在她的K99阶段，她将继续参加每周的实验室会议和部门/相关研讨会，并在部门研讨会以及内布拉斯加州西部爱荷华州退伍军人事务研究研讨会系列每年提出。通过这项培训计划，候选人将能够过渡到独立，拥有独特的研究利基的专业知识，研究环境暴露后气道炎症和解决方案中的生物活性脂质代谢和信号传导。

 DESCRIPTION (provided by applicant) In agriculture industries, organic dust exposures trigger harmful airway inflammation, and individuals employed in concentrated animal feeding operations experience work-related inflammatory lung diseases, including chronic bronchitis and obstructive airway diseases. Existing therapeutics do not adequately treat the resulting airway disease. Thus, novel preventative or treatment schemes are vitally needed to combat the deleterious inflammatory effects of these exposures. The health benefits of diets high in omega-3 fatty acids (ω-3 FA) are well recognized but incompletely understood. Recent studies reveal certain ω-3 FA derivatives actively attenuate and resolve inflammatory processes; these specialized pro-resolving mediators (SPM) may be key to the beneficial effects of ω-3 FA. Harnessing the protective properties of ω-3 FA and SPM in therapeutic strategies could revolutionize the way we combat debilitating airway diseases. However, it is not fully understood how ω-3 FA and SPM function in the lung to limit inflammation and promote resolution. Therefore, the objective of the proposed research is to determine the role of ω-3 FA and their SPM derivatives in modulating organic dust-induced airway inflammation. It is hypothesized that ω-3 FA and their SPM derivatives regulate the active resolution of airway inflammation following exposures to agricultural dusts. To test this hypothesis, three specific aims are proposed. The focus of aim 1 is to delineate the effects of ω-3 FA supplementation on mitigating organic dust-induced acute and chronic airway inflammation in vivo. Aim 2 focuses on determining the mechanisms by which ω-3 FA exert anti-inflammatory and pro-resolving actions in organic dust-stimulated BECs. Aim 2a will determine the role of cyclooxygenase and lipoxygenase enzymatic pathways in regulating lipid mediator production in docosahexaenoic acid (DHA)-supplemented bronchial epithelial cells stimulated by DE. Aim 2b will define how DHA treatment alters TAK1-mediated inflammatory signaling in DE-stimulated BECs. Aim 3 of the application examines how ω-3 FA regulates chronic organic dust-induced T cell and macrophage activation. These investigations are expected to have important positive impacts by demonstrating how ω-3 FA actively regulates lung inflammation resolution. These results will reveal the potential for interventions involving ω-3 FA supplementation in preventing and treating a broad array of inflammatory airway diseases. In addition to performance of the above proposed research aims, a major goal of this application is to provide training in the bioactive lipids field to aid in the candidate's successful transitio from a postdoctoral fellow to an independent investigator. Her long-term career objective is to become a successful, independent research investigator in academia. The candidate plans to develop a productive research program that adds depth and vitality to the field of environmental health research with a focus on immunity and natural, endogenous means of disease prevention and alleviation. Her NIEHS-F32 has provided training in environmental health and respiratory toxicology, while this K99 would allow her to develop expertise in bioactive lipid signaling and metabolism, including learning new techniques that will be critical to her success in this field. The candidate's academic research environment is well suited to providing her with the necessary training proposed in this application. The pulmonary research group at the University of Nebraska Medical Center has six NIH-, three CDC-, and two VA-funded basic research projects relevant to the candidate's proposed area of research training and investigation. The collaborative nature of the academic campus allows for frequent interfacing with basic scientists, clinicians, and other trainees on a daily basis. The Durham Research Center II built in 2009 includes state-of-the-art research core facilities and complete animal facilities available with th capacity to perform all advanced techniques described in the proposal. The candidate's proposed career development activities are aimed at bolstering her knowledge and experience in the bioactive lipids research field, and increasing her lab management and supervisory skills. During my K99 phase the candidate will work directly with Dr. Bruce Levy at the Harvard Medical School to learn how to prepare and handle samples for liquid chromatography-mass spectrometry technologies and analyze output for lipid metabolite profiling. She will participate i the Jackson Laboratory's "The Whole Scientist" 4-day workshop to bolster her skills and experience in mentoring, communication, lab management, and entrepreneurship. She will participate in the ATS postgraduate course, "Using `omics to study lung disease" to increase her capacity to derive robust, meaningful mechanistic data from the in vivo and other models utilized in my studies. The candidate plans to attend the 15th Eicosanoid Research Foundation's International Conference on Bioactive Lipids in Cancer Inflammation, and Related Diseases in addition to the annual ATS meetings. She will also attend relevant Keystone Symposia offered, i.e. the symposium on Systems Biology of Lipid Metabolism and/or the annual Kern Lipid Conferences, based on relevance. Throughout her K99 phase, she will continue to attend weekly lab meetings and departmental/relevant seminars, and present annually in departmental seminars as well as the Nebraska-Western Iowa Veterans Affairs Research Seminar Series. With this training program, the candidate will be able to transition to independence with expertise in a unique research niche investigating bioactive lipid metabolism and signaling in airway inflammation and resolution following environmental exposures.