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

项目摘要 慢性阻塞性肺疾病（COPD）与特发性肺纤维化的演变 (IPF)可能与遗传变异、表观遗传决定因素、环境因素或其 交互. COPD和IPF的遗传和表观遗传决定因素可能不是孤立的， 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 在本PPG的第一个周期中，我们将重点关注线粒体和几丁质酶途径作为潜在的分子生物学途径。 影响个体是否发生COPD或IPF的开关。我们假设一个分子网络 调节线粒体和几丁质酶蛋白质的遗传和表观遗传决定因素赋予差异 吸烟者易患COPD或IPF。此外，我们假设线粒体和几丁质酶 这些通路影响COPD和IPF的异质性表现。为了研究 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 利用我们在COPD和IPF（包括肺）中的人群和遗传/表观遗传资源 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 血浆和肺生物标本中的蛋白质和线粒体途径蛋白质，并检测其与COPD的相关性 和IPF及其相关表型。我们将识别遗传变异、线粒体特征和DNA 影响肺和血液中几丁质酶和线粒体途径蛋白表达的甲基化标记 样本，并确定这些变异是否也与COPD和/或IPF相关。我们将确定 线粒体和几丁质酶途径内部和之间的网络关系，通过使用基于相关性的 网络、基因调控网络和蛋白质-蛋白质相互作用网络。内部的主要网络关系 以及线粒体和几丁质酶途径之间的关系将使用基于CRISPR的功能方法进行验证 在肺上皮细胞、单核细胞-巨噬细胞和成纤维细胞中，读出细胞死亡、纤维化、壳多糖 组成部分，线粒体功能和炎症，以确定共享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.