Integrative 'Omics of Transcriptome Complexity in COPD

项目总结 Aabida Saferali博士是一位专注于呼吸系统疾病遗传学的学术研究员，他的 职业生涯的首要目标是成为一名独立的调查员，具备综合运用经济学的技能 提高对慢性阻塞性疾病生物学认识和临床治疗的技术 肺部疾病(COPD)是全球主要的死亡原因之一。拟议的研究结合了 她以前在遗传学和转录学方面的经验，以及在长阅读测序方面的培训，高级 综合经济学和生物统计学，以解决确定致病原因的根本问题 Gwas基因座中的基因。这一提议的假设是通过RNA进行转录调控 剪接在COPD的发生发展过程中起着重要的作用。这一点将由 利用来自两个肺部疾病表型良好的研究的现有数据：COPD基因和肺组织 研究联盟。具体目标：(1)表征吸烟者和吸烟者的基因表达和剪接 检测COPD病例对照状态和肺功能的相关性；(2)发现表达 数量性状基因座(QTL)、剪接QTL和转录率QTL以及用这些数据解释 以及(3)使用长阅读RNA测序来表征全长异构体 与疾病相关，并明确识别剪接模式。创新的研究计划，它 使用新的方法来表征剪接，将识别与替代方案有关的COPD Gwas基因座 拼接。它伴随着一份培训计划，该计划将为Saferali博士提供完成 研究目标，以及过渡到独立并提交R01扩展的经验 应用长读测序技术研究慢性阻塞性肺疾病患者的异构体多样性。特别值得一提的是，Saferali博士有四个 培训目标建立在她现有的呼吸遗传学背景的基础上。(一)加强自身建设 生物统计学和统计基因组学知识；(2)拓展她的综合组学技能；(3) 在长阅读测序的生成、分析和解释方面获得经验和专业知识 数据；(4)加深对研究设计和指导的理解。她得到了一位 具有互补技能和成功的指导职业生涯的指导团队，与她一起 经验和培训将保证这项提议的成功。这些发现可能会为 开发有针对性的治疗和个性化方法，同时探索一种新的方法来 解决当今该领域最重要的分析挑战之一：亚型多样性的表征 使用RNA测序。

PROJECT SUMMARY Aabida Saferali, PhD, is an academic researcher with a focus on the genetics of respiratory diseases, whose overarching career goal is to become an independent investigator with the skill set to utilize integrative ‘omic techniques for the improved biological understanding and clinical management of chronic obstructive pulmonary disease (COPD), one of the leading causes of death worldwide. The proposed research combines her prior experience in genetics and transcriptomics with training in long-read sequencing, advanced integrative ‘omics, and biostatistics, in order to address the fundamental issue of identifying disease causing genes in GWAS loci. The hypothesis of this proposal is that transcriptional regulation through RNA splicing plays an important role in COPD development and pathogenesis. This will be explored by leveraging existing data from two well-phenotyped studies of lung disease: COPDGene and the Lung Tissue Research Consortium. Specific Aims: (1) characterizing gene expression and splicing in smokers and testing for associations with COPD case-control status and lung function; (2) discovering expression quantitative trait loci (QTLs), splice QTLs and transcript ratio QTLs and using these data to explain GWAS findings; and (3) using long-read RNA sequencing to characterize full-length isoforms associated with disease and definitively identifying splicing patterns. The innovative research plan, which utilizes novel methodologies to characterize splicing, will identify COPD GWAS loci involved in alternative splicing. It is accompanied by a training plan, which will provide Dr. Saferali with the skills to complete the research aims, as well as the experience to transition to independence and submit an R01 expanding upon the characterization of isoform diversity in COPD using long-read sequencing. In particular Dr. Saferali has four training goals which build upon her existing background in respiratory genetics. (1) To strengthen her knowledge of biostatistics and statistical genomics; (2) to expand her integrative ‘omics skill set; (3) to gain experience and expertise in the generation, analysis and interpretation of long-read sequencing data; and (4) to deepen her understanding of study design and mentoring. She is supported by a mentoring team with complementary skillsets and successful mentoring careers, which, together with her experience and training, will guarantee the success of this proposal. The findings may pave the way for the development of targeted therapeutics and personalized approaches, while exploring a novel methodology to address one of the most important analytic challenges in the field today: characterization of isoform diversity using RNA sequencing.