Integrative 'Omics of Transcriptome Complexity in COPD

项目概要 Aabida Saferali 博士是一位学术研究员，专注于呼吸系统疾病的遗传学研究。 总体职业目标是成为一名独立调查员，具备利用综合“组学”的技能 提高慢性阻塞性肺疾病生物学认识和临床管理的技术 肺部疾病（COPD）是全球主要死亡原因之一。拟议的研究结合了 她之前在遗传学和转录组学方面拥有丰富的经验，接受过长读测序、高级测序方面的培训 综合组学和生物统计学，以解决识别致病原因的根本问题 GWAS 基因座中的基因。该提案的假设是通过 RNA 进行转录调控 剪接在COPD的发展和发病机制中起着重要作用。这将由 利用来自两项表型良好的肺部疾病研究的现有数据：COPDGene 和 Lung Tissue 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 测试与慢性阻塞性肺病病例对照状态和肺功能的关联； (2)发现表达 数量性状位点 (QTL)、剪接 QTL 和转录本比率 QTL，并使用这些数据来解释 GWAS 发现； (3) 使用长读长 RNA 测序来表征全长亚型 与疾病相关并明确识别剪接模式。该创新研究计划， 利用新颖的方法来表征剪接，将识别参与替代的 COPD GWAS 位点 拼接。它附有培训计划，该计划将为 Saferali 博士提供完成以下任务的技能 研究目标，以及过渡到独立并提交 R01 扩展的经验 使用长读长测序表征 COPD 的亚型多样性。 Saferali 博士特别有四个 培训目标建立在她现有的呼吸遗传学背景之上。 （一）强化她的力量 生物统计学和统计基因组学知识； (2) 扩展她的综合“组学”技能； (3) 至 获得长读长测序的生成、分析和解释方面的经验和专业知识 数据； (4) 加深她对研究设计和指导的理解。她得到了一个人的支持 辅导团队具有互补的技能和成功的辅导生涯，与她一起 经验和培训将保证该提案的成功。研究结果可能为 开发靶向治疗和个性化方法，同时探索一种新的方法 解决当今该领域最重要的分析挑战之一：异构体多样性的表征 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.