Role of polyunsaturated fatty acids in pulmonary fibrosis

项目摘要/摘要 我的目标是成为间质性肺病(ILD)的独立临床和翻译研究员 我在这份为期5年的K23职业发展奖申请表中概述了这一点。我的提议的中心目标是建立 Omega-3脂肪酸摄入量(在血浆磷脂中测量)，作为特发性肺疾病的新危险因素 纤维化(IPF)。IPF是一种慢性间质性肺疾病，发生在缺乏可用药物治疗的老年人中。 预后差，中位生存期3~4年。这项建议建立在我的初步数据基础上 显示较高的血浆磷脂omega-3脂肪酸水平与较少的亚临床ILD相关 在社区居住的成年人中，CT和ILD相关住院和死亡率的风险较低。其中 临床诊断为ILD的成年人，我的数据显示omega-3脂肪酸血浆磷脂水平 与较高的用力肺活量和运动能力相关。我的数据与老鼠的研究结果一致 表明服用omega-3脂肪酸可以减轻肺损伤和纤维化，这可能是由 生产omega-3衍生的促分解脂质介体(SPM)。在伊姆雷·诺思博士的指导下，我 建议研究血浆磷脂omega-3脂肪酸水平及其代谢物之间的关系 (SPM)与成人IPF的疾病严重程度和进展的关系。我会将循环中的omega-3水平进行关联 从肺中提取SPM，并根据不同的SPM水平确定不同的基因表达谱和途径。 我已经制定了一份严格的5年职业发展计划，其中包括呼吸道流行病学的培训(联合 导师：巴尔博士)脂肪酸生物学(共同导师：莱廷格博士)、生物统计学(共同导师：马博士)和临床- 翻译研究和ILD(主要导师：Noth博士)，这将使我成为一名临床和 以患者为中心的研究中的翻译独立调查者。通过实现这项K23建议的目标，我 将多不饱和脂肪酸确立为IPF的一个新的修饰因素，使我能够识别出特定的 将从omega-3治疗中受益最大的表型，并设计和实施未来的临床试验。

PROJECT SUMMARY/ABSTRACT My goal is to become an independent clinical and translational researcher in interstitial lung disease (ILD) which I outline in this 5-year K23 Career Development Award application. The central goal of my proposal is to establish omega-3 fatty acid intake (as measured in plasma phospholipids), as a novel risk factor in idiopathic pulmonary fibrosis (IPF). IPF is a chronic form of interstitial lung disease in older adults with few available medical therapies and a poor prognosis with a median survival of 3 to 4 years. This proposal builds upon my preliminary data showing that higher plasma phospholipid levels of omega-3 fatty acids were associated with less subclinical ILD on CT and a lower risk of ILD-related hospitalization and mortality among community-dwelling adults. Among adults with clinically diagnosed ILD, my data shows omega-3 fatty acid plasma phospholipid levels were correlated with higher forced vital capacity and exercise capacity. My data are consistent with mouse studies that show administration of omega-3 fatty acids attenuates lung injury and fibrosis which may be driven by production of omega-3 derived pro-resolving lipid mediators (SPMs). Under the mentorship of Dr. Imre Noth, I propose to examine the associations of plasma phospholipid omega-3 fatty acid levels and their metabolites (SPMs) with disease severity and progression in adults with IPF. I will correlate circulating levels of omega-3 derived SPMs with the lung and identify distinct gene expression profiles and pathways by different SPM levels. I have crafted a rigorous 5-year career development plan that includes training in respiratory epidemiology (co- mentor: Dr. Barr) fatty acid biology (co-mentor: Dr. Leitinger), biostatistics (co-mentor: Dr. Ma), and clinical- translational research and ILD (primary mentor: Dr. Noth) that will position me to become a clinical and translational independent investigator in patient-oriented research. By achieving the aims of this K23 proposal, I will establish polyunsaturated fatty acids as a novel modifying factor in IPF leading me to identify specific phenotypes that will benefit the most from omega-3 therapy and design and implement future clinical trials.