Genomic Profiling of Early Pulmonary Fibrosis

项目总结/摘要 目的：本项目的目标是确定临床前肺纤维化的分子标志物， 开发预测模型以检测早期特发性肺纤维化（IPF）。与健康的关系：IPF是 其特征在于肺实质的进行性瘢痕形成，从发生时起的中位生存期为3年。 诊断，影响全世界500万患者，并且患病率正在增加。很少有被批准的 治疗IPF，无治愈性药物治疗。家族性间质性肺炎（FIP）患者的亲属 发生IPF的风险高于一般人群。大多数IPF患者在以下情况下被诊断为 这种疾病是晚期的，IPF的早期诊断可以检测到肺组织更完整的患者， 早期干预的目标，可能将IPF治疗模式从缓解转变为预防。 基本原理：初步数据显示，16%的FIP亲属有临床前肺纤维化的证据。 外周血基因表达的分析表明，那些临床前肺纤维化的患者， 不同的基因表达谱。假设：外周血分子标记可用于识别 高危个体的临床前肺纤维化和该高危队列中肺纤维化的早期发现 是疾病进展的前兆具体目标1：发现和验证表观遗传标记， 外周血中的蛋白质与早期纤维化相关，并确定显着的关系 表观遗传标记与差异基因表达。聚焦差异甲基化区域和血浆 既往与IPF相关的蛋白质、外周血DNA甲基化和血浆蛋白水平将被 以识别与早期肺纤维化相关的区域。现有的基因表达数据将 用于表征DNA甲基化和基因表达之间的关系。具体目标2：利用 从基因表达数据和目标1中发现的重要分子标记， 将开发一个模型来识别该高危队列中的早期肺纤维化。具体目标3： 确定FIP肺纤维化的患病率、进展和影像学特征 亲属，并在研究期间对新发肺纤维化患者进行预测模型检验 期在初次胸部CT扫描五年后，FIP亲属将接受重复胸部成像， 抽血我们将确定（1）自初次扫描以来发生新发纤维化的受试者数量，以及（2） 进行性纤维化的放射学特征。其次，我们将检查我们的预测模型的有效性 目的2中的目的，以确定那些新发纤维化的患者。职业发展：候选人有长期的- 长期致力于肺纤维化的学术医学和转化研究。她是一个 支持性研究小组和具有长期研究IPF历史的机构。亲身体验， 全面的指导，跨机构的合作，以及拟议的教学培训将准备 首席研究员，在晚期肺部疾病领域从事独立的转化研究。

PROJECT SUMMARY/ABSTRACT Objectives: The goal of this project is to identify molecular markers of preclinical pulmonary fibrosis in order to develop a predictive model to detect early idiopathic pulmonary fibrosis (IPF). Relationship to health: IPF is characterized by progressive scarring of the lung parenchyma, has a median survival of 3 years from time of diagnosis, affects 5 million patients worldwide, and is increasing in prevalence. There are few approved therapies for IPF and no curative medical therapies. Relatives of Familial Interstitial Pneumonia (FIP) patients are at higher risk than the general population of developing IPF. Most patients with IPF are diagnosed when the disease is advanced—earlier diagnosis of IPF would detect patients with more intact lung tissue and reveal targets for early intervention, potentially shifting the IPF treatment paradigm from palliation to prevention. Rationale: Preliminary data show that 16% of FIP relatives have evidence of preclinical pulmonary fibrosis. Analysis of peripheral blood gene expression illustrates that those with preclinical pulmonary fibrosis have a distinct gene expression profile. Hypothesis: Peripheral blood molecular signatures can be utilized to identify preclinical pulmonary fibrosis in at-risk individuals and early findings of pulmonary fibrosis in this at-risk cohort are a precursor to progressive disease. Specific Aim 1: Discover and validate epigenetic marks and proteins in peripheral blood associated with early fibrosis and determine the relationship of significant epigenetic marks to differential gene expression. Focusing on differentially methylated regions and plasma proteins previously associated with IPF, peripheral blood DNA methylation and plasma protein levels will be measured to identify regions associated with early pulmonary fibrosis. Existing gene expression data will be used to characterize the relationship between DNA methylation and gene expression. Specific Aim 2: Utilizing significant molecular markers from gene expression data and those discovered in Aim 1, a predictive model to identify early pulmonary fibrosis in this at-risk cohort will be developed. Specific Aim 3: Determine the prevalence, progression, and radiographic characteristics of pulmonary fibrosis in FIP relatives and test our predictive model in those with de novo pulmonary fibrosis during the study period. Five years after their initial thoracic CT scan, FIP relatives will undergo repeat thoracic imaging and blood draw. We will determine (1) the number of subjects developing de novo fibrosis since initial scan and (2) radiographic features of progressive fibrosis. Secondarily, we will examine the validity of our predictive model from Aim 2 to identify those who develop de novo fibrosis. Career Development: The candidate has a long- term commitment to academic medicine and translational research in pulmonary fibrosis. She is a member of a supportive research group and institution with a long history of studying IPF. The hands-on experience, comprehensive mentorship, cross-institutional collaboration, and didactic training proposed will prepare the principal investigator for an independent career in translational research in the field of advanced lung diseases.