Role of High Density Lipoproteins in Interstitial Lung Disease

高密度脂蛋白在间质性肺疾病中的作用

• 批准号: 10322195
• 负责人: Anna Podolanczuk
• 金额: $ 17.16万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-02 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322195
• 关键词: Adult; Affect; Age; Ancillary Study; Animal Model; Antioxidants; Apolipoprotein A-I; Apolipoprotein A-II; Apolipoproteins A; Area; Attenuated; Award; Biological Assay; Biological Markers; Biology; Biometry; Blood Vessels; Chest; Cholesterol; Clinical; Clinical Investigator; Communities; Conduct Clinical Trials; Coronary Arteriosclerosis; Data; Death Rate; Development Plans; Diagnosis; Disease; Disease Progression; Elderly; Endothelium; Enrollment; Epithelial Cells; Extracellular Matrix; FDA approved; Family; Family member; Fibrosis; First Degree Relative; Funding; Future; Gender; Goals; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Image; Inflammasome; Inflammation; Intercellular adhesion molecule 1; Interleukin-1 beta; Interleukin-18; Interstitial Lung Diseases; Intervention Studies; K-Series Research Career Programs; Knowledge; Lead; Link; Lipoproteins; Lung diseases; Matrilysin; Measures; Mediating; Medical; Mentors; Mentorship; Multi-Ethnic Study of Atherosclerosis; Mus; National Heart, Lung, and Blood Institute; Outcome; Oxidative Stress; Pathway interactions; Patients; Plasma; Play; Prevention; Primary Prevention; Prospective cohort study; Proteins; Proteome; Proteomics; Public Health; Pulmonary Fibrosis; Pulmonary Inflammation; Regulation; Research Personnel; Research Project Grants; Risk; Risk Factors; Role; Secondary Prevention; Serum; Structure; Structure of parenchyma of lung; Therapy Clinical Trials; Training; Translational Research; Work; X-Ray Computed Tomography; alveolar epithelium; antifibrotic treatment; attenuation; career; career development; clinical diagnosis; clinical epidemiology; comparison group; data modeling; density; design; disease phenotype; early detection biomarkers; epidemiology study; fibrotic interstitial lung disease; idiopathic pulmonary fibrosis; imaging biomarker; lung injury; macrophage; middle age; monocyte; mortality; non-smoking; novel; particle; patient oriented; patient oriented research; prevent; preventive intervention; prospective; protective factors; research and development; symptomatic improvement; thrombogenesis; translational scientist

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.

项目概要/摘要 在这份为期 5 年的 K23 职业发展奖申请中，我建议指导研究和职业 发展成为间质性肺的独立临床和转化研究者 疾病。该研究项目的目标是确定高密度脂蛋白在特发性肺疾病中的作用 纤维化 (IPF)，一种致命的肺部疾病，每 200 名老年人中就有 1 人受到影响，中位生存期为 3-5 年 从诊断。目前尚无药物治疗可以改善 IPF 患者的症状或逆转纤维化。 该建议建立在我的初步数据之上，该数据显示高水平的高密度胆固醇 (HDL-C) 与社区居民 CT 上肺损伤、炎症和纤维化（亚临床 ILD）的减少相关 参加 NHLBI 资助的动脉粥样硬化多种族研究的成年人。这些数据与动物一致 模型数据显示，载脂蛋白 A-I（ApoA-I；HDL 的主要成分）治疗可减弱肺功能 纤维化。因此，在 David Lederer 博士的指导下，我建议研究以下关联： HDL 及其主要成分（ApoA-I、ApoA-II 和 paroxonase-1）与临床结果和血清 Dr. 招募的临床诊断 IPF 成人的肺损伤、炎症和重塑的生物标志物。 Lederer 的 FAR-ILD 研究（ILD 风险家庭；R01 HL103676-06，2016 年 12 月得分第 5 个百分位）。我会 还探索了结构（在 Emily Chen 博士的实验室使用定量蛋白质组学）和功能（使用 在 Alan Tall 博士的实验室中对 IPF 成人以及两个比较者中的 HDL 颗粒进行巨噬细胞流出测定 组：参加 FAR-ILD 研究的患有亚临床 ILD 的一级家庭成员以及健康对照。 在导师的指导下，我制定了一个 5 年职业发展计划，其中包括以下方面的培训： 脂蛋白生物学（共同导师：Tall博士）、定量蛋白质组学（共同导师：陈博士）、临床流行病学 （Lederer 博士）和生物统计学（RoyChoudhury 博士）。在该奖项的最后两年我将申请 R01 资助 并过渡到独立。拟议的活动将使我做好准备进行以患者为导向的和 转化研究发现 IPF 和其他 ILD 的新风险因素。我也会准备设计和 开展针对新途径（包括本 K23 提案中发现的途径）的临床试验，以预防和 治疗间质性肺病。

项目成果

Nonlinear associations between computed tomography-measures of adiposity and long pentraxin-3 in the Multi-Ethnic Study of Atherosclerosis.

• DOI: 10.1002/osp4.708
• 发表时间: 2024-02
• 期刊: OBESITY SCIENCE & PRACTICE
• 影响因子: 2.2
• 作者: Anderson, Michaela R.;Kim, John S.;Podolanczuk, Anna;Ding, Jingzhong;Al-Naamani, Nadine;Allison, Matthew;Christie, Jason;Diamond, Joshua
• 通讯作者: Diamond, Joshua

Angiotensin Receptor Blockers and Subclinical Interstitial Lung Disease: The MESA Study.

血管紧张素受体阻滞剂和亚临床间质性肺病：MESA 研究。

• DOI: 10.1513/annalsats.201903-198rl
• 发表时间: 2019
• 期刊: Annals of the American Thoracic Society
• 影响因子: 8.3
• 作者: Gannon,WhitneyD;Anderson,MichaelaR;Podolanczuk,AnnaJ;Kawut,StevenM;Michos,ErinD;Cottin,Vincent;Kreuter,Michael;Raghu,Ganesh;Barr,RGraham;Lederer,DavidJ
• 通讯作者: Lederer,DavidJ

Prevalence, Risk Factors, and Outcomes of Adult Interstitial Lung Abnormalities: A Systematic Review and Meta-Analysis.

成人间质性肺异常的患病率、危险因素和结果：系统回顾和荟萃分析。

• DOI: 10.1164/rccm.202302-0271oc
• 发表时间: 2023
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7
• 作者: Grant-Orser,Amanda;Min,Bohyung;Elmrayed,Seham;Podolanczuk,AnnaJ;Johannson,KerriA
• 通讯作者: Johannson,KerriA

Clinical characteristics associated with small airways disease in systemic sclerosis.

与系统性硬化症小气道疾病相关的临床特征。

• DOI: 10.1177/23971983221083882
• 发表时间: 2022
• 期刊: Journal of scleroderma and related disorders
• 影响因子: 2
• 作者: Varma,Sanskriti;Yun,JaeHee;Kim,JohnS;Podolanczuk,AnnaJ;Patel,NinaM;Bernstein,ElanaJ
• 通讯作者: Bernstein,ElanaJ