Role of High Density Lipoproteins in Interstitial Lung Disease

项目总结/摘要 在这份为期5年的K23职业发展奖的申请中，我建议指导研究和职业生涯 发展导致职业生涯作为一个独立的临床和翻译研究者在间质性肺 疾病本研究项目的目的是确定高密度脂蛋白在特发性肺动脉高压中的作用。 肺纤维化（IPF），一种致死性肺部疾病，200名老年人中有1人受累，中位生存期为3-5年 从诊断。目前没有改善IPF患者症状或逆转纤维化的药物治疗。 这个建议是建立在我的初步数据基础上的，这些数据表明，高水平的高密度胆固醇（HDL-C） 与社区居民CT显示的肺损伤、炎症和纤维化（亚临床ILD）减少相关 参加NHLBI资助的多种族动脉粥样硬化研究的成年人。这些数据与动物一致。 模型数据显示，用载脂蛋白A-I（ApoA-I; HDL的主要成分）治疗可减弱肺 纤维化因此，在大卫·莱德勒博士的指导下，我建议研究 HDL及其主要组分（ApoA-I、ApoA-II和帕氧磷酶-1）与临床结局和血清 入组Dr. Lederer的FAR-ILD研究（ILD风险家庭; R 01 HL 103676 -06，2016年12月评分为第5百分位数）。我会 我还探索了结构（使用艾米丽陈博士实验室的定量蛋白质组学）和功能（使用 Alan Tall博士实验室中的巨噬细胞流出试验）对IPF成人以及两种对照药物中HDL颗粒的影响 组：入组FAR-ILD研究的亚临床ILD一级家族成员和健康对照。 在导师的指导下，我制定了一个5年职业发展计划，其中包括以下培训： 脂蛋白生物学（共同导师：Tall博士），定量蛋白质组学（共同导师：Chen博士），临床流行病学 (Dr. Lederer）和生物统计学（RoyChoudhury博士）。在获奖的最后两年，我将申请R 01资助 过渡到独立。拟议的活动将使我做好准备， 转化研究，以发现IPF和其他ILD的新风险因素。我也将准备设计和 开展针对新途径的临床试验（包括K23提案中发现的途径），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.