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）：间质性肺部疾病（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，最多影响100,000名美国人。在不可逆的肺纤维化发作之前，寻找有效的肺纤维化疗法是难以捉摸的，可能需要鉴定和研究该疾病的早期阶段。不幸的是，大多数受影响的人都患有先进的肺纤维化，阻碍了了解导致ILD的早期事件的努力。 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正在2010 - 12年重复。我们已经在MESA和哥伦比亚IPF研究中进行了初步研究，这表明HAA升高是亚临床ILD的新成像生物标志物。现在，我们建议进行其他研究，以证明升高HAA的生物学和生理与临床ILD相似。我们还建议对HAA升高的全基因组联系和关联研究。因此，我们将（a）在2002年至2012年之间进行的剩余MESA心脏CT扫描中进行测量，以建立亚临床ILD的纵向案例定义，（（b）测量SP-A，SP-D，SP-D，MMP-1和MMP-7的血清水平，581例横截面和493个纵向案例和493例Compitional和Subclinical Case complinical and Complinical ILD和Sclininical ILD（c）。测量100个MESA参与者中的静息和运动功能。我们建议使用这些新数据以及来自MESA，MESA家族和MESA共享研究的现有遗传联系和关联数据，以完成三个具体目标：具体目标1：确定HAA升高病例是否具有AEC损伤的血清标记（SP-A和SP-D）标记（SP-A和SP-D）和ECM重塑（MMP-1和MMP-1和MMP-7）。特定目的2：测试MESA参与者的假设，即HAA升高的个体与HAA正常患者相比损害了肺功能。具体目的3：在MESA和MESA家庭研究中进行定量（HAA）和定性（HAA）表型的统计遗传分析。如果我们达到目标，我们提出的研究将建立升高的HAA作为一种新型的基于CT的ILD生物标志物，以在未来的ILD分子和遗传基础的研究中使用。我们的遗传学目的旨在提供新的数据，以刺激对早期ILD发病机理机制的额外研究，并有可能发现新颖的途径和治疗靶标，以防止肺纤维化。