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.