Role of polyunsaturated fatty acids in pulmonary fibrosis

项目总结/摘要 我的目标是成为间质性肺病（ILD）的独立临床和转化研究人员， 我在这份为期5年的K23职业发展奖申请中概述了这一点。我的建议的中心目标是建立 ω-3脂肪酸摄入量（以血浆磷脂测定）作为特发性肺动脉高压的新危险因素 纤维化（IPF）。IPF是一种老年人慢性间质性肺病，可用的药物治疗很少 预后差，中位生存期为3至4年。这个建议是建立在我的初步数据基础上的 显示较高的omega-3脂肪酸血浆磷脂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相关住院和死亡的风险较低。之间 临床诊断为ILD的成人，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。我的数据和老鼠的研究一致 这表明ω-3脂肪酸的施用减轻了肺损伤和纤维化， 产生ω-3衍生的促分解脂质介质（SPM）。在Imre Noth博士的指导下，我 建议检查血浆磷脂omega-3脂肪酸水平及其代谢产物之间的关系 （SPM）与IPF成人患者疾病严重程度和进展的关系。我会把血液中的omega-3 衍生的SPM与肺，并通过不同SPM水平鉴定不同的基因表达谱和途径。 我制定了一个严格的5年职业发展计划，其中包括呼吸流行病学培训（合作）， 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- 转化研究和ILD（主要导师：博士诺斯），这将使我成为一个临床和 翻译独立研究者在以病人为导向的研究。通过实现K23提案的目标，我 将多不饱和脂肪酸作为IPF的一种新的修饰因子， 研究人员将研究最能从omega-3治疗中受益的表型，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.