Integrative 'Omics of Transcriptome Complexity in COPD

COPD 转录组复杂性的综合组学

基本信息

批准号：
10375562
负责人：
Aabida Saferali
金额：
$ 17.8万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10375562
关键词：
Address Alleles Alternative Splicing Biological Biometry Blood Blood specimen Cause of Death Cells Chronic Obstructive Pulmonary 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 Respiratory Disease 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

项目摘要

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，拟议的研究结合了这一点。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该提议的假设是通过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，这将通过以下方式进行探索。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 研究联盟的具体目标：(1) 表征吸烟者和吸烟者的基因表达和剪接 (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 结果；(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的创新研究计划。利用新颖的方法来表征剪接，将识别参与替代的 COPD GWAS 位点它附有培训计划，该计划将为 Saferali 博士提供完成拼接的技能。研究目标，以及过渡到独立并提交 R01 扩展的经验 Saferali 博士特别提出了四种使用长读长测序来表征 COPD 异构体多样性的方法。基于她现有的遗传呼吸背景的培训目标 (1) 加强她的能力。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) 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。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该提案的成功，研究结果可能为该提案铺平道路。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。