Integrative 'Omics of Transcriptome Complexity in COPD

COPD 转录组复杂性的综合组学

• 批准号: 10189836
• 负责人: Aabida Saferali
• 金额: $ 17.81万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10189836
• 关键词: Address; Alleles; Alternative Splicing; Biological; Biometry; Blood; Blood specimen; Cause of Death; Cells; Chronic Obstructive Airway Disease; Clinical Management; Complement; Data; Data Set; Development; Disease; Disease susceptibility; Doctor of Philosophy; Drug Targeting; Environmental Risk Factor; FDA approved; Gene Expression; Gene Expression Regulation; Generations; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genomics; Genotype; Goals; Knowledge; Lead; Length; Lung; Lung diseases; Mentors; Methodology; Nucleic Acid Regulatory Sequences; Pathogenesis; Pathway interactions; Pattern; Phenotype; Play; Protein Isoforms; Quantitative Trait Loci; RNA Splicing; Research; Research Design; Research Personnel; Research Priority; Role; Sampling; Smoker; Smoking; Spliced Genes; Structure; Structure of parenchyma of lung; Susceptibility Gene; Techniques; Testing; Tissue Sample; Tissues; Training; Transcript; Transcriptional Regulation; Translational Research; Variant; Whole Blood; Work; career; case control; cigarette smoking; disorder risk; experience; gene product; genetic variant; genome wide association study; genomic locus; improved; innovation; insight; novel; personalized approach; pulmonary function; respiratory; skills; success; targeted treatment; transcriptome; transcriptome sequencing; transcriptomics

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.

项目摘要 Aabida Saferali博士是一位专注于呼吸系统疾病遗传学的学术研究人员， 首要的职业目标是成为一名独立的调查员，具备利用综合经济学的技能。 提高慢性阻塞性肺疾病生物学认识和临床管理的技术 慢性阻塞性肺病（COPD）是全球主要的死亡原因之一。该研究结合了 她之前在遗传学和转录组学方面的经验，以及在长读测序方面的培训， 综合组学和生物统计学，以解决确定疾病原因的根本问题 GWAS基因座中的基因。该提议的假设是，通过RNA的转录调节 剪接在COPD的发展和发病中起重要作用。这将由以下人员进行探讨： 利用来自两个良好的肺部疾病表型研究的现有数据：COPD基因和肺组织 研究联盟。具体目的：（1）表征吸烟者和吸烟者中的基因表达和剪接， 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和转录比QTL，并利用这些数据来解释 GWAS发现;和（3）使用长读段RNA测序来表征全长同种型 与疾病相关并明确识别剪接模式。创新研究计划， 利用新的方法学来表征剪接，将确定参与替代选择的COPD GWAS基因座。 拼接它附有一个培训计划，将为Saferali博士提供完成 研究目标，以及过渡到独立的经验，并提交R 01扩展 使用长读段测序表征COPD中的同种型多样性。特别是Saferali博士有四个 培训目标建立在她现有的呼吸遗传学背景之上。(1)加强她 生物统计学和统计基因组学的知识;（2）扩展她的综合组学技能;（3） 获得长读序测序生成、分析和解读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 辅导团队具有互补的技能和成功的辅导职业生涯，这与她一起， 经验和培训，将保证这一建议的成功。这些发现可能为 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。