Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by breathlessness due to airflow obstruction. COPD is the third leading cause of death worldwide. So far, none of the existing pharmacological treatments for COPD can stop the progressive decline in lung function. Drug repurposing is the application of existing approved therapeutic compounds for new disease indications, which may reduce the cost and time of new drug development. So far, there is not any systematic multi-omics data integration for drug repurposing in COPD. The goal of this project is to develop a systems biology pipeline for the identification of biological-relevant gene targets with drug repurposing potential for COPD treatment using multi-omics integration. Here we implemented a computational methodology to identify drug repurposing targets for COPD. We integrated multi-omics COPD data including, genome, transcriptome, proteome, metabolome, interactome data, and drug-target information. A distance-based network model was created to rank the potential candidate genes. Fifty genes were prioritized as COPD signature genes for their overall proximity to signature genes identified at all omics levels. Forty of them may be considered as “druggable” targets. Literature search reported CRCX4 – Plerixafor as one prioritized targets-gene pair for drug repurposing. The bone marrow stimulant Plerixafor is currently being evaluated for COPD treatment in clinical trials, suggesting that our pipeline is finding promising drug repurposing targets. Our work, for the first time, applied a systematic approach integrating multiple omics data to find drug repurposing targets for COPD. / Pharmaceutical Sciences

Chronic lung diseases including Chronic Obstructive Pulmonary Disease (COPD), Idiopathic Pulmonary Fibrosis (IPF) and lung cancer are major causes of morbidity and mortality in the United States due to high incidence and limited therapeutic options. In order to address this critical issue, I have leveraged RNA sequencing and integrative genomics to define disease-associated transcriptomic changes which could be potentially targeted to lead to new therapeutics. We sequenced the lung transcriptome of subjects with IPF (n=19), emphysema (n=19, a subtype of COPD), or neither (n=20). The expression levels of 1770 genes differed between IPF and control lung, and 220 genes differed between emphysema and control lung (p<0.001). Upregulated genes in both emphysema and IPF were enriched for the p53/hypoxia pathway. These results were validated by immunohistochemistry of select p53/hypoxia proteins and by GSEA analysis of independent expression microarray experiments. To identify regulatory events, I constructed an integrative miRNA target prediction and anticorrelation miRNA-mRNA network, which highlighted several miRNA whose expression levels were the opposite of genes differentially expressed in both IPF and emphysema. MiR-96 was a highly connected hub in this network and was subsequently overexpressed in cell lines to validate several potential regulatory connections. Building upon these successful experiments, I next sought to define gene expression changes and the miRNA-mRNA regulatory network in never smoker lung cancer. Large and small RNA was sequenced from matched lung adenocarcinoma tumor and adjacent normal lung tissue obtained from 22 subjects (8 never, 14 current and former smokers). I identified 120 genes whose expression was modified uniquely in never smoker lung tumors. Using a repository of gene-expression profiles associated with small bioactive molecules, several compounds which counter the never smoker tumor signature were identified in silico. Leveraging differential expression information, I again constructed an mRNA-miRNA regulatory network, and subsequently identified a potential never smoker oncomir has-mir-424 and its transcription factor target FOXP2. In this thesis, I have identified genes, pathways and the miRNA-mRNA regulatory network that is altered in COPD, IPF, and lung adenocarcinoma among never smokers. My findings may ultimately lead to improved treatment options by identifying targetable pathways, regulators, and therapeutic drug candidates. / 2017-02-01T00:00:00Z

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京都大学 / 新制・課程博士 / 博士(医学) / 甲第24967号 / 医博第5021号 / 新制||医||1069(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊達 洋至, 教授 江木 盛時, 教授 川上 浩司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Introduction: Mobile health applications (mHealth apps) may support people’s chronic obstructive pulmonary disease (COPD) self-management. Current research has demonstrated the promising effects of mHealth apps for people with COPD but there is still limited information on these apps’ characteristics and qualities, especially those in the public domain. Therefore, there is the need to use a standardized evaluation framework to: 1) describe characteristics and qualities of COPD apps from past studies; 2) characterize the features and qualities of public COPD apps; and 3) determine the appropriateness of public COPD apps from the perspective of clinicians and patients living with COPD. Methods: The mHealth Index and Navigation Database (MIND) framework, an objective evaluation tool was applied across studies. Project 1: A systematic review was conducted, including randomized controlled trials investigating interactive mHealth apps for people living with chronic lung diseases (CLD). Project 2: An evaluation study of the public marketplace (Android and Apple app stores) was conducted. Free mHealth apps created specifically for COPD self-management were included. Project 3: Reviewed COPD apps were presented to stakeholders in an infographic format. A RAND/UCLA Appropriateness Method (RAM) was used to collect feedback from stakeholders on the state of public COPD apps. Results: Many of the COPD apps trialed in past studies have inconsistent reports of their features and qualities, with many publicly unavailable. Most public COPD apps lacked clinical evidence to support their use and have questionable qualities. Stakeholders agreed that public COPD apps were mostly inappropriate but did not dismiss the need to discuss their potential in COPD care plans. Significance: This thesis project advocates for the partnership with multiple heath disciplines and patient-participants for app evaluations to gain stronger understanding of their potential. Future opportunities may include exploring other apps for lung diseases to promote stakeholder engagement throughout the process. / Thesis / Candidate in Philosophy