Leveraging Variant-perturbed Gene Regulation to Support Precision Medicine in COPD

利用变异扰动的基因调控支持慢性阻塞性肺病的精准医疗

• 批准号: 10583539
• 负责人: Kimberly Renee Glass
• 金额: $ 79.71万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583539
• 关键词: Address; Biological; Blood; Blood specimen; Chronic Obstructive Pulmonary Disease; Clinical; Complex; DNA Sequence; Data; Development; Disease; Disease model; Disease susceptibility; Environment; Epigenetic Process; Gene Expression Regulation; Genes; Genetic Variation; Goals; Individual; Link; Lung diseases; Maps; Messenger RNA; Methodology; Methods; Modeling; Molecular; Network-based; Observational Study; Outcome; Pathogenesis; Pathway Analysis; Pharmaceutical Preparations; Phenotype; Play; Proteins; Quantitative Trait Loci; RNA; Regulation; Research; Role; Sampling; Smoking; Software Tools; Structure; Structure of parenchyma of lung; Testing; Therapeutic; Therapeutic Intervention; Tissue Sample; Tissues; Trans-Omics for Precision Medicine; Translating; Variant; Whole Blood; affection; clinical application; data integration; genetic association; genetic variant; genome wide association study; genomic locus; insight; lung development; lung health; multiple omics; network models; novel; novel therapeutic intervention; novel therapeutics; open source; precision medicine; preservation; programs; response; targeted treatment; therapeutic target; therapeutically effective; transcription factor; transcriptome sequencing; translational impact; treatment strategy

Summary/Abstract Micro-ribonucleic acids (miRNAs) are crucial for normal lung development, lung health, and have been implicated in lung diseases, including Chronic Obstructive Pulmonary Disease (COPD). In addition, recent studies have identified miRNAs as potential therapeutic targets for COPD. miRNAs play an important role in gene regulation. miRNAs act within a complex regulatory structure that involves other biological molecules, including transcription factors, proteins, messenger RNAs (mRNAs), and other epigenetic mechanisms, all of which may be under the influence of genetic variants. A number of genetic variants have been identified as important for COPD through Genome-Wide Association Studies (GWAS). However, substantial computational and methodological challenges impede both linking genetic variants to altered molecular mechanisms and identifying therapeutic interventions that can effectively target these mechanisms for clinical impact. Understanding the complex structure of gene regulation, including by and of miRNAs, and how it is altered in disease or in response to a genetic variant, is critical for developing effective, precision-medicine based therapeutic strategies in COPD. In this project, we hypothesize that network-based methods, which model the collective response of biological molecules, have the potential to identify novel therapeutic strategies for COPD. Our goal is to leverage the predictions made by regulatory network models in a Connectivity Map analysis to identify potential therapeutic interventions for COPD. To accomplish this goal, we will first develop a network approach to model regulation by and of miRNAs using existing mRNA and miRNA expression data from blood samples in COPDGene. We will also generate miRNA expression data in lung tissue from the Lung Tissue Research Consortium (LTRC). We will use these data to assess changes in miRNAs related to COPD and to quantify associations between miRNAs and genetic variants. Co-expression, regulatory, and genetic-association networks will be developed to support multi-Omics predictions relevant to COPD. Network analysis results will be analyzed in the context of drug response profiles from the Connectivity Map to identify potential treatment strategies. The outcome of this project will be a deeper understanding of the regulatory role of miRNAs in COPD, how disease-specific miRNA regulation is altered in the context of COPD GWAS variants, and predictions for novel therapeutic strategies for COPD. The methods developed in the project will also support the broader goal of developing precision-medicine strategies for COPD.

摘要/摘要 微核糖核酸 (miRNA) 对于正常的肺部发育和肺部健康至关重要，并且已被 与肺部疾病有关，包括慢性阻塞性肺病（COPD）。此外，最近 研究已确定 miRNA 是 COPD 的潜在治疗靶点。 miRNA 在以下方面发挥着重要作用 基因调控。 miRNA 在涉及其他生物分子的复杂调控结构中发挥作用， 包括转录因子、蛋白质、信使 RNA (mRNA) 和其他表观遗传机制，所有这些 这可能是受到遗传变异的影响。已鉴定出许多遗传变异 通过全基因组关联研究 (GWAS) 对 COPD 具有重要意义。然而，大量的计算 方法学上的挑战阻碍了将遗传变异与改变的分子机制联系起来 确定可以有效针对这些机制产生临床影响的治疗干预措施。 了解基因调控的复杂结构，包括 miRNA 的调控，以及它是如何改变的 疾病或对遗传变异的反应，对于开发有效的、基于精准医学的药物至关重要 COPD 的治疗策略。 在这个项目中，我们假设基于网络的方法可以模拟生物的集体反应 分子，有潜力确定慢性阻塞性肺病的新治疗策略。我们的目标是利用 通过连接图分析中的监管网络模型做出的预测，以识别潜在的治疗方法 慢性阻塞性肺病 (COPD) 的干预措施。为了实现这一目标，我们将首先开发一种网络方法来进行模型监管 使用 COPDGene 中血液样本中现有的 mRNA 和 miRNA 表达数据来分析 miRNA。我们 还将生成来自肺组织研究联盟 (LTRC) 的肺组织中的 miRNA 表达数据。 我们将使用这些数据来评估与 COPD 相关的 miRNA 的变化，并量化之间的关联 miRNA 和遗传变异。将开发共表达、调控和遗传关联网络 支持与 COPD 相关的多组学预测。网络分析结果将在以下背景下进行分析 连接地图中的药物反应概况可确定潜在的治疗策略。这件事的结果 项目将更深入地了解 miRNA 在 COPD 中的调节作用，疾病特异性 miRNA 如何 COPD GWAS 变异的背景下调节发生了改变，并预测了新的治疗策略 慢性阻塞性肺病。该项目开发的方法也将支持发展精准医疗的更广泛目标 慢性阻塞性肺病的策略。