Elucidating the Genomic Determinants of Outcomes in Idiopathic Pulmonary Fibrosis

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Idiopathic pulmonary fibrosis (IPF) is a rare, but devastating interstitial lung disease characterized by a progressive decline in lung function and a median survival of 3-5 years after diagnosis. Despite the poor prognosis, IPF follows a highly variable clinical course, whereby most patients experience gradual disease progression, some demonstrate relative stability and a small group dies from rapidly progressive disease. Anti- fibrotic therapies were recently approved for the treatment of IPF, but it remains unclear which IPF phenotypes derive the most benefit. Recent advances in genomic technology provide an excellent opportunity to improve our understanding of IPF progression and treatment response. In this proposal, I aim to take advantage of these genomic advances to identify single nucleotide polymorphisms (SNPs) linked to relevant IPF outcomes. I will do this using DNA samples collected from patients enrolled in past and current IPF clinical trials, along with two large IPF registries. My central hypothesis is that patients genetically predisposed to death, disease progression and treatment response can be prospectively identified using SNPs linked to these endpoints. I will first conduct a genome-wide survival analysis to identify SNPs linked to early IPF mortality. I will then genotype relevant susceptibility and outcome-associated SNPs in several clinical trial datasets to determine whether they predict relevant trial endpoints, including pulmonary function decline and hospitalization. Finally, I will genotype SNPs at potential pharmacogenetic loci to determine whether such SNPs modulate the response to anti-fibrotic therapy. This work will advance my long-term career goal of incorporating genetics into clinical decision-making in patients with IPF. Concurrently I will pursue a career development plan that will provide outstanding mentorship, hands-on laboratory experience and additional training in genetic epidemiology, statistical genetics, and bioinformatics. This K23 award is vital to successful completion of this proposal and timely execution of my career development plan, as it will provide the time necessary to meet the realistic milestones that have set in conjunction with my advisory committee. Ultimately this award will allow me to successfully compete for R01 funding aimed at advancing my long-term goal above.