Subclinical Interstitial Lung Disease in MESA

MESA 的亚临床间质性肺病

• 批准号: 8435401
• 负责人: David J. Lederer
• 金额: $ 71.95万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-15 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8435401
• 关键词: Affect; African; African American; Age; Alveolar; American; Area; Atherosclerosis; Autopsy; Biological Markers; Biology; Cardiac; Chinese People; Chronic Obstructive Airway Disease; Cigarette; Clinical; Code; Data; Development; Diffuse; Disease; Epithelial Cells; Ethnic group; European; Event; Exercise; Extracellular Matrix; Family; Family Study; Fibrosis; Funding; Future; Genes; Genetic; Genotype; Goals; Hamman-Rich syndrome; Hispanics; Image; Individual; Inflammation; Injury; Interstitial Collagenase; Interstitial Lung Diseases; Investigation; Lead; Lung; Lung Transplantation; Lung diseases; Matrilysin; Matrix Metalloproteinases; Measures; Mediating; Medical; Minority; Molecular Genetics; National Heart, Lung, and Blood Institute; Non-Malignant; Outcome; Participant; Pathogenesis; Pathway interactions; Phenotype; Physiology; Proteins; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactant-Associated Protein D; Research; Resources; Respiratory physiology; Rest; Risk; Risk Factors; Serum; Single Nucleotide Polymorphism; Staging; Testing; Time; United States; Walking; X-Ray Computed Tomography; advanced disease; attenuation; base; case control; cell injury; cohort; comparison group; cost effective; design; effective therapy; genetic analysis; genetic association; genetic linkage; genome wide association study; genome-wide linkage; inflammatory marker; innovation; mortality; new therapeutic target; novel; population based; prevent; public health relevance; therapeutic target

DESCRIPTION (provided by applicant): The interstitial lung diseases (ILDs) are characterized by alveolar injury, inflammation, and fibrosis. Idiopathic pulmonary fibrosis (IPF), the most common and deadly fibrotic ILD, affects up to 100,000 Americans. The search for an effective therapy for lung fibrosis has been elusive and may require identification and investigation of an earlier stage of the disease, prior to the onset of irreversible lung fibrosis. Unfortunately, most affected individuals present with advanced lung fibrosis, hampering efforts to understand the early events leading to ILD. We recently identified subclinical ILD using a CT-based phenotype (high attenuation areas, HAA) in the Multi-Ethnic Study of Atherosclerosis (MESA), an NHLBI-funded population-based cohort of 6,814 participant's age 45-84 years of European, African, Hispanic, and Chinese descent who underwent longitudinal cardiac CT scanning between 2000 and 2007. CT scans are being repeated in 2010-12. We have performed preliminary studies in MESA and the Columbia IPF Study suggesting that elevated HAA is novel imaging biomarker of subclinical ILD. We now propose to perform additional studies to demonstrate that the biology and physiology of elevated HAA resembles that of clinical ILD. We also propose to perform genome-wide linkage and association studies of elevated HAA. Therefore, we will (a) measure HAA in the remaining MESA cardiac CT scans performed between 2002 and 2012 to establish a longitudinal case definition of subclinical ILD, (b) measure serum levels of SP-A, SP-D, MMP-1, and MMP-7 in 581 cross-sectional cases and 493 longitudinal cases of subclinical ILD and a comparison group of 1,200 MESA participants, and (c) measure resting and exercise lung function in 100 MESA participants. We propose to use these new data and existing genetic linkage and association data from the MESA, MESA Family, and MESA SHARe studies to accomplish three Specific Aims: Specific Aim 1: To determine if cases with elevated HAA have higher serum levels of markers of AEC injury (SP-A and SP-D) and ECM remodeling (MMP-1 and MMP-7) compared to a comparison group. Specific Aim 2: To test the hypothesis in MESA participants that individuals with elevated HAA have impaired lung function compared to those with normal HAA. Specific Aim 3: To perform statistical genetic analyses of quantitative (HAA) and qualitative (elevated HAA) phenotypes of subclinical ILD in the MESA and MESA Family studies. If we achieve our Aims, our proposed study will establish elevated HAA as a novel CT- based biomarker of ILD to be used in future studies of the molecular and genetic basis of ILD. Our genetics Aim is designed to provide new data to stimulate additional research into the mechanisms of early ILD pathogenesis with the potential to discover novel pathways and therapeutic targets to prevent lung fibrosis.

描述（由申请人提供）：间质性肺疾病（ILD）的特征是肺泡损伤、炎症和纤维化。特发性肺纤维化 (IPF) 是最常见和致命的纤维化 ILD，影响多达 100,000 名美国人。寻找肺纤维化的有效疗法一直难以实现，可能需要在不可逆肺纤维化发生之前识别和研究疾病的早期阶段。不幸的是，大多数受影响的个体都患有晚期肺纤维化，这阻碍了了解导致 ILD 的早期事件的努力。我们最近在动脉粥样硬化多种族研究 (MESA) 中使用基于 CT 的表型（高衰减区，HAA）识别出亚临床 ILD，这是一个由 NHLBI 资助的基于人群的队列，共有 6,814 名年龄为 45-84 岁的欧洲、非洲参与者2000 年至 2007 年间接受纵向心脏 CT 扫描的西班牙裔和华裔。CT 扫描正在重复进行2010-12。我们在 MESA 和哥伦比亚 IPF 研究中进行了初步研究，表明 HAA 升高是亚临床 ILD 的新型影像生物标志物。我们现在建议进行更多研究，以证明 HAA 升高的生物学和生理学与临床 ILD 相似。我们还建议对升高的 HAA 进行全基因组连锁和关联研究。因此，我们将 (a) 测量 2002 年至 2012 年间进行的剩余 MESA 心脏 CT 扫描中的 HAA，以建立亚临床 ILD 的纵向病例定义，(b) 测量 SP-A、SP-D、MMP-1 的血清水平，和 MMP-7 在 581 例亚临床 ILD 横断面病例和 493 例纵向病例以及由 1,200 名 MESA 参与者组成的对照组中进行测量，以及 (c) 测量静息和锻炼 100 名 MESA 参与者的肺功能。我们建议利用这些新数据以及来自 MESA、MESA Family 和 MESA SHARe 研究的现有遗传连锁和关联数据来实现三个具体目标： 具体目标 1：确定 HAA 升高的病例是否具有较高的 AEC 标记物血清水平与对照组相比，损伤（SP-A 和 SP-D）和 ECM 重塑（MMP-1 和 MMP-7）。具体目标 2：测试 MESA 参与者的假设，即与 HAA 正常的人相比，HAA 升高的个体肺功能受损。具体目标 3：对 MESA 和 MESA 家族研究中亚临床 ILD 的定量（HAA）和定性（HAA 升高）表型进行统计遗传分析。如果我们实现了我们的目标，我们提出的研究将把升高的 HAA 作为一种基于 CT 的新型 ILD 生物标志物，用于未来 ILD 分子和遗传基础的研究。我们的遗传学目标旨在提供新数据，以刺激对早期 ILD 发病机制的进一步研究，并有可能发现预防肺纤维化的新途径和治疗靶点。