Genetic and Genomic Characterization of the Occurrence and Progression of Interstitial Lung Abnormalities

间质性肺异常发生和进展的遗传和基因组特征

• 批准号: 9982375
• 负责人: MICHAEL H. CHO
• 金额: $ 80.04万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982375
• 关键词: Address; Adult; Age; Cicatrix; Clinical; Clinical Trials; Collaborations; Data; Detection; Development; Disease; Early treatment; Exercise; Fibrosis; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genomics; Goals; Impairment; Individual; Institution; Lead; Lung; MUC5B gene; Malignant Neoplasms; Medical; Mutation; Participant; Pathogenesis; Patient-Focused Outcomes; Patients; Pattern; Pharmaceutical Preparations; Physiological; Population; Population Research; Positioning Attribute; Prevalence; Pulmonary Fibrosis; Pulmonology; Radiology Specialty; Reporting; Research; Respiratory physiology; Risk; Risk Factors; Role; Survival Rate; Syndrome; Telomerase; Testing; Translating; Treatment outcome; Variant; Work; X-Ray Computed Tomography; base; chest computed tomography; cohort; disorder risk; genetic predictors; genetic profiling; genetic risk factor; genetic variant; genome-wide; genomic data; genomic locus; genomic predictors; genomic profiles; genomic signature; idiopathic pulmonary fibrosis; improved; improved outcome; insight; interstitial; mortality; mortality risk; novel; outcome forecast; peripheral blood; predictive modeling; prevent; risk variant; screening

7. Project Summary The primary objective of this proposal is to characterize the genetic and genomic profiles of those who develop, and progress from, early stages of pulmonary fibrosis (PF). Idiopathic pulmonary fibrosis (IPF), the most common and severe form of PF, has a mortality rate comparable to that of many end-stage malignancies. Despite advances in medical therapy for IPF, it is becoming increasing recognized that further attempts to improve outcomes for patients with IPF will need to additionally focus on preventing very early, but detectable, stages of PF from progressing to the end-stages of PF that help to define IPF. Recent evidence has demonstrated that research participants with particular patterns chest CT abnormalities (termed interstitial lung abnormalities [ILA]) can have a syndrome similar to that observed in IPF patients. Insights from this work include the fact that although ILA are more prevalent (7-9% in adults > age 50) than IPF is reported to be (0.002-0.04% of the population), research participants with ILA can have genetic predictors noted in IPF patients, restrictive physiologic and exercise impairments, radiologic progression, accelerated lung function decline, and an increased risk for death. Based on these findings, we hypothesize that ILA, in some cases, represent and early/mild stage of IPF which will result in a substantial overlap in the genetic and genomic predictors between these two conditions. Furthermore, we hypothesize that comprehensive genetic and genomic profiles of early/mild stages of PF, will not only improve our understanding of early disease pathogenesis, but can also be translated into clinical tests that will help to determine those who are at the greatest risk to develop, and progress, from PF. To address these hypotheses we propose the following specific aims: Aim 1) Can genetic profiles be identified in those who develop, and progress from, early stages of PF? Aim 2) Can lung and peripheral blood genomic profiles be identified in those who develop, and progress from, early stages of PF? And Aim 3) Can the integration of clinical, as well as genetic and genomic data improve our understanding of early disease pathogenesis, and enable early disease detection for, PF? The results of these studies will improve our understanding of early disease pathogenesis in PF, as well as setting the stage for trials aimed at the early institution novel and existing medical therapies in those at risk for IPF.

七、项目概要 该提案的主要目标是表征遗传和基因组图谱 肺纤维化 (PF) 早期阶段的发展和进展患者。 特发性肺纤维化 (IPF) 是最常见和最严重的 PF 形式，具有以下特点： 死亡率与许多终末期恶性肿瘤相当。尽管取得了进展 IPF 的药物治疗，人们越来越认识到进一步尝试 改善 IPF 患者的治疗结果还需要重点关注预防 从进展到 PF 末期的早期但可检测的阶段，有助于 定义 IPF。最近的证据表明，研究参与者具有特定的 胸部 CT 异常（称为间质性肺异常 [ILA]）可能有 与 IPF 患者中观察到的综合征相似。这项工作的见解包括以下事实 据报道，虽然 ILA 比 IPF 更常见（50 岁以上成人中为 7-9%） 是（人口的 0.002-0.04%），患有 ILA 的研究参与者可能有遗传 IPF 患者中注意到的预测因素，限制性生理和运动障碍， 放射学进展、肺功能加速下降以及风险增加 死亡。基于这些发现，我们假设 ILA 在某些情况下代表并 IPF 的早期/轻度阶段，这将导致遗传和遗传的大量重叠 这两种情况之间的基因组预测因子。此外，我们假设 PF 早期/轻度阶段的全面遗传和基因组图谱，不仅 提高我们对早期疾病发病机制的理解，但也可以转化为 进行临床测试，这将有助于确定哪些人的患病风险最大， 和进步，来自 PF。为了解决这些假设，我们提出以下具体建议 目标： 目标 1) 能否在那些发展和进步的人中鉴定遗传图谱？ PF 的早期阶段？目标 2) 能否鉴定肺和外周血基因组图谱 那些患有 PF 早期阶段并取得进展的人？目标 3) 可以吗 临床、遗传和基因组数据的整合提高了我们对 早期疾病发病机制，并实现早期疾病检测，PF？结果 这些研究将提高我们对 PF 早期疾病发病机制的理解，因为 并为针对早期机构新颖和现有医学的试验奠定基础 对有 IPF 风险的患者进行治疗。