Role of High Density Lipoproteins in Interstitial Lung Disease

项目摘要/摘要 在这份申请为期5年的K23职业发展奖的申请书中，我建议进行有指导的研究和职业 发展成为间质肺的独立临床和翻译研究人员 疾病。本研究的目的是确定高密度脂蛋白在特发性肺疾病中的作用。 纤维化(IPF)是一种致命的肺部疾病，每200名老年人中就有一人患病，中位生存期为3-5年 从诊断出来的。目前还没有改善IPF患者症状或逆转纤维化的药物治疗。 这项建议是基于我的初步数据显示，高水平的高密度胆固醇(HDLC)是 社区居民CT上肺损伤、炎症和纤维化(亚临床ILD)的减少 成年人参加了NHLBI资助的动脉粥样硬化多种族研究。这些数据与动物的数据一致 模型数据显示，用载脂蛋白A-I(ApoA-I；高密度脂蛋白的主要成分)治疗会使肺变弱 纤维化症。因此，在大卫·莱德尔博士的指导下，我提议研究 高密度脂蛋白及其主要成分(ApoA-I、ApoA-II和Paroxonase-1)与临床结局和血清的关系 临床诊断为IPF的成人的肺损伤、炎症和重塑的生物标志物在DR中登记。 Leder的Far-ILD研究(ILD高危家庭；R01 HL103676-06,2016年12月第5个百分位数)。这就做 还要探索结构(使用艾米丽·陈博士实验室的定量蛋白质组学)和功能(使用 在Alan Tall博士的实验室中的巨噬细胞外排试验)成人IPF患者的高密度脂蛋白颗粒以及在两个对照仪器中的 分组：参加Far-ILD研究的亚临床ILD患者的一级家庭成员和健康对照组。 在导师的指导下，我制定了一份为期5年的职业发展计划，其中包括 脂蛋白生物学(共同导师：Tall博士)、定量蛋白质组学(共同导师：陈博士)、临床流行病学 和生物统计学(Roychoudhury博士)。在获奖的最后两年，我将申请R01资金 并过渡到独立。拟议的活动将使我做好准备，进行以病人为本的 翻译研究，以发现IPF和其他ILDS的新风险因素。我还将准备设计和 针对新途径(包括K23提案中未涉及的途径)进行临床试验，以预防和 治疗ILD。

PROJECT SUMMARY/ABSTRACT In this application for a 5-year K23 Career Development Award, I propose mentored research and career development leading toward a career as an independent clinical and translational investigator in interstitial lung disease. The goal of this research project is to identify the role of high-density lipoprotein in idiopathic pulmonary fibrosis (IPF), a fatal lung disease that affects 1 out of 200 older adults and has a median survival of 3-5 years from diagnosis. Currently there is no medical therapy that improves symptoms or reverses fibrosis in IPF patients. This proposal builds upon my preliminary data showing that high levels of high density cholesterol (HDL-C) are associated with a reduction in lung injury, inflammation and fibrosis (subclinical ILD) on CT in community-dwelling adults enrolled in the NHLBI-funded Multi-Ethnic Study of Atherosclerosis. These data are consistent with animal model data showing that treatment with apolipoprotein A-I (ApoA-I; the main component of HDL) attenuates lung fibrosis. Under the mentorship of Dr. David Lederer, I am therefore proposing to examine the associations of HDL and its main components (ApoA-I, ApoA-II, and paroxonase-1) with clinical outcomes and serum biomarkers of lung injury, inflammation and remodeling in adults with clinically-diagnosed IPF enrolled in Dr. Lederer's FAR-ILD study (Families At-Risk for ILD; R01 HL103676-06, scored 5th percentile Dec 2016). I will also explore the structure (using quantitative proteomics in Dr. Emily Chen's lab) and function (using a macrophage efflux assay in Dr. Alan Tall's lab) of HDL particles in adults with IPF as well as in two comparator groups: first-degree family members with subclinical ILD enrolled in the FAR-ILD study, and healthy controls. With guidance from my mentors, I have crafted a 5-year career development plan that includes training in lipoprotein biology (co-mentor: Dr. Tall), quantitative proteomics (co-mentor: Dr. Chen), clinical epidemiology (Dr. Lederer), and biostatistics (Dr. RoyChoudhury). In the last two years of the award I will apply for R01 funding and transition to independence. The proposed activities will prepare me to conduct patient-oriented and translational research to discover novel risk factors for IPF and other ILDs. I will also be prepared to design and conduct clinical trials targeting novel pathways (including those uncovered in this K23 proposal) to prevent and treat ILD.