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

项目总结 慢性阻塞性肺疾病与特发性肺纤维化的不同发展阶段 吸烟者的IPF可能与遗传变异、表观遗传决定因素、环境因素或其 互动。COPD和IPF的遗传和表观遗传决定因素可能不是孤立运行的 影响相互作用的基因和蛋白质的分子网络。基于小鼠和人类研究的进展 在这个PPG的第一个周期中，我们将重点关注线粒体和几丁质酶通路作为潜在的分子 影响个人是否患上慢性阻塞性肺疾病或肺间质纤维化的开关。我们假设一个分子网络 调控线粒体和几丁质酶蛋白的遗传和表观遗传决定因素存在差异 吸烟者患COPD或IPF的易感性。此外，我们假设线粒体和几丁质酶 多种途径影响COPD和IPF的异质性表现。为了调查这一差异 COPD和IPF的易感性以及这些途径对COPD和IPF亚型的影响，我们将 利用我们基于人类群体和遗传/表观遗传资源在慢性阻塞性肺疾病和IPF，包括肺 组织研究联盟(LTRC)和多个复制群体。我们将测量一组几丁质酶 血浆和肺组织中线粒体途径蛋白及其与COPD的相关性 和IPF及其相关表型。我们将确定遗传变异、线粒体特征和DNA 影响几丁质酶和线粒体途径蛋白在肺和血液中表达的甲基化标志 并确定这些变异是否也与COPD和/或IPF有关。我们将确定 基于相关性的线粒体和几丁质酶通路内部和之间的网络关系 网络、基因调控网络和蛋白质-蛋白质相互作用网络。内部的关键网络关系 线粒体和几丁质酶之间的通路将使用基于CRISPR的功能方法进行验证 肺上皮细胞、单核巨噬细胞和成纤维细胞的细胞死亡、纤维化、壳聚糖体读数 成分、线粒体功能和炎症，以确定共同和不同的网络决定因素 IPF和COPD。

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.