Integrating Omics, Networks, and Functional Studies in COPD and IPF

整合 COPD 和 IPF 的组学、网络和功能研究

• 批准号: 10172314
• 负责人: Edwin K Silverman
• 金额: $ 37.98万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-06 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10172314
• 关键词: Address; Biological; Blood; Blood specimen; Cell Death; Cells; Characteristics; Chitinase; Chronic Obstructive Airway Disease; Cigarette Smoker; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Code; DNA Methylation; Data; Development; Environmental Risk Factor; Epigenetic Process; Epithelial Cells; Fibroblasts; Fibrosis; Gene Proteins; Genetic; Haplogroup; Heterogeneity; Human; Individual; Inflammation; Link; Lung; Measures; Mitochondria; Molecular; Mus; National Heart, Lung, and Blood Institute; Network-based; Participant; Pathway Analysis; Pathway interactions; Phenotype; Plasma; Population; Predisposition; Process; Proteins; Proteomics; Pulmonary Emphysema; Regulator Genes; Research; Resources; Sampling; Smoker; Structure of parenchyma of lung; Susceptibility Gene; System; Systems Analysis; Testing; Trans-Omics for Precision Medicine; Untranslated RNA; Validation; Variant; X-Ray Computed Tomography; base; biobank; chest computed tomography; disorder subtype; genetic variant; genome sequencing; idiopathic pulmonary fibrosis; knockout gene; macrophage; monocyte; population based; programs; protein protein interaction; study population; transcriptome sequencing; whole genome

PROJECT SUMMARY The variable development of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) among smokers could relate to genetic variants, epigenetic determinants, environmental factors, or their interactions. Rather than operating in isolation, genetic and epigenetic determinants of COPD and IPF likely influence molecular networks of interacting genes and proteins. Based on progress in murine and human studies in the first cycle of this PPG, we will focus on mitochondrial and chitinase pathways as potential molecular switches that impact whether individuals develop COPD or IPF. We hypothesize that a molecular network of genetic and epigenetic determinants regulating mitochondrial and chitinase proteins confers differential susceptibility of smokers to develop COPD or IPF. In addition, we hypothesize that mitochondrial and chitinase pathways influence the heterogeneous manifestations of COPD and IPF. In order to investigate the differential susceptibility to develop COPD and IPF and the impact of these pathways on COPD and IPF subtypes, we will leverage our human population-based and genetic/epigenetic resources in COPD and IPF, including the Lung Tissue Research Consortium (LTRC) and multiple replication populations. We will measure a panel of chitinase and mitochondrial pathway proteins in plasma and lung biospecimens and test for their association with COPD and IPF and their related phenotypes. We will identify genetic variants, mitochondrial characteristics, and DNA methylation marks that influence expression of chitinase and mitochondrial pathway proteins in lung and blood samples and determine whether these variants are also associated with COPD and/or IPF. We will identify network relationships within and between the mitochondrial and chitinase pathways by using correlation-based networks, gene regulatory networks, and protein-protein interaction networks. Key network relationships within and between mitochondrial and chitinase pathways will be validated using CRISPR-based functional approaches in lung epithelial cells, monocyte-macrophages, and fibroblasts with readouts of cell death, fibrosis, chitosome components, mitochondrial function, and inflammation to identify shared and divergent network determinants of IPF and COPD.

项目摘要 慢性阻塞性肺疾病（COPD）和特发性肺纤维化的可变发育 （IPF）吸烟者可能与遗传变异，表观遗传决定因素，环境因素或其有关 互动。 COPD和IPF的遗传和表观遗传决定因素可能不是孤立地运行 影响相互作用基因和蛋白质的分子网络。基于鼠和人类研究的进步 在该PPG的第一个周期中，我们将重点放在线粒体和几丁质酶途径上，作为电势分子 转换个人是开发COPD还是IPF。我们假设一个分子网络 调节线粒体和几丁质酶蛋白的遗传和表观遗传决定因素赋予差异 吸烟者开发COPD或IPF的敏感性。另外，我们假设线粒体和几丁质酶 途径影响COPD和IPF的异质表现。为了研究差异 开发COPD和IPF的敏感性以及这些途径对COPD和IPF子类型的影响，我们将 利用我们在COPD和IPF中基于人群的人群和遗传/表观遗传资源，包括肺 组织研究联盟（LTRC）和多重复制人群。我们将测量一组几丁质酶 血浆和肺生物测量中的线粒体途径蛋白，并测试其与COPD的关联 IPF及其相关表型。我们将确定遗传变异，线粒体特征和DNA 甲基化标记会影响肺和血液中几丁质酶和线粒体途径蛋白的表达 样本并确定这些变体是否也与COPD和/或IPF相关联。我们将确定 通过使用基于相关的线粒体和几丁质酶途径内和之间的网络关系 网络，基因调节网络和蛋白质 - 蛋白质相互作用网络。关键网络关系 线粒体和几丁质酶途径之间将使用基于CRISPR的功能方法验证 在肺上皮细胞中，单核细胞巨噬细胞和成纤维细胞，具有细胞死亡，纤维化，壳体的读数 组件，线粒体功能和炎症，以识别共享和不同的网络决定因素 IPF和COPD。