Elucidating the genomic determinants of outcomes in idiopathic pulmonary fibrosis

项目摘要/摘要 特发性肺纤维化(IPF)是一种罕见但毁灭性的间质性肺疾病，其特征是 肺功能进行性下降，确诊后中位生存期为3-5年。尽管很穷 预后方面，IPF遵循高度多变的临床过程，大多数患者经历渐进性疾病。 在进展中，一些人表现出相对稳定，一小部分人死于快速进展的疾病。反- 纤维化疗法最近被批准用于治疗特发性肺纤维化，但目前尚不清楚哪些特发性肺纤维化表型。 获得最大的利益。基因组技术的最新进展提供了一个极好的机会来改进 我们对IPF进展和治疗反应的理解。在这项提议中，我的目标是利用 这些基因组的进展是确定与相关IPF结果相关的单核苷酸多态(SNPs)。我 将使用从过去和当前IPF临床试验中登记的患者收集的DNA样本来完成这项工作，以及 两个大型IPF登记处。我的中心假设是，患者在遗传上容易死亡、疾病 可以使用与这些终点相关的单核苷酸多态来前瞻性地识别进展和治疗反应。这就做 首先，进行全基因组生存分析，以确定与IPF早期死亡相关的SNPs。然后我会分型的 在几个临床试验数据集中确定相关的易感性和结果相关的SNPs 他们预测相关的试验终点，包括肺功能下降和住院。最后，我会 确定潜在药物遗传基因座上的SNPs的基因型，以确定这些SNPs是否调节对 抗纤维化治疗。成功完成这项提案将导致定制SNP的开发 为IPF临床试验的设计提供信息并具有识别新基因的高潜力的芯片 日作为治疗靶点。 我的长期职业目标是将遗传学融入IPF患者的临床决策中， 具体地说，临床试验招募和治疗选择。为了朝着这一目标取得进展，相关的 用来对IPF队列进行风险分层和药物遗传学测试的遗传标记必须首先 被指认出来。为了做到这一点，已经制定了一项职业发展计划，将提供出色的指导， 实践实验室经验和遗传流行病学、统计遗传学和 生物信息学。我将从基因组学、间质性肺病和临床领域的领导者那里获得指导。 和翻译调查。一个由不同背景的人组成的咨询委员会 汇编了关于临床登记和生物信息库管理的具体指导， 实验室培训、统计遗传学和结果建模。这个K23奖项对于成功是至关重要的 完成这项建议并及时执行我的职业发展计划，因为这将提供时间 这是实现与我的咨询委员会共同制定的现实里程碑所必需的。最终 这一奖项将使我能够成功地竞争R01资金，旨在推进我的长期目标。 加州大学戴维斯分校的研究环境是全国最好的之一，包括NIH资助的临床 以及由NIEHS P30计划资助的职业发展核心--翻译科学中心(CTSC) 在环境健康科学(ESH)，比较呼吸生物学和医学中心 (CCRBM)和综合遗传学和基因组学研究生小组(IGG)。加州大学戴维斯分校的CTSC是 最初的12个由NIH支持的全国中心，提供生物信息学、IRB提交和 进行由研究人员发起的临床试验。EHS职业发展核心提供了至关重要的帮助 为初级调查人员启动研究职业生涯，包括导师研讨会，资助写作援助 以及以实验室领导力为重点的研讨会。CCRBM，其中包括许多合作调查人员 专注于肺纤维化，还提供临床和高级生物统计学的研究生课程。IGG 提供遗传流行病学、统计遗传学和生物信息学的附加课程。再加上一个 加州大学戴维斯分校的ILD项目规模庞大且久负盛名，在患者-- 以研究为导向，并为开展这项提议提供了理想的环境。 好了！

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. Successful completion of this proposal will lead to the development of customized SNP chips that inform the design of IPF clinical trials and has a high potential to identify novel genes that may one day serve as therapeutic targets. My long-term career goal is to incorporate genetics into clinical decision-making in patients with IPF, specifically clinical trial enrollment and therapeutic selection. To make progress towards this goal, the relevant genetic markers with which to stratify IPF cohorts for risk-stratification and pharmacogenetic testing must first be identified. To do this, a career development has been devised that will provide outstanding mentorship, hands-on laboratory experience and additional training in genetic epidemiology, statistical genetics and bioinformatics. I will draw mentorship from leaders in the field of genomics, interstitial lung disease and clinical and translational investigation. An advisory committee composed of individuals with diverse backgrounds has been assembled to provide specific guidance with regard to clinical registry and biorepository management, laboratory training, statistical genetics and outcomes modeling. 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. The research environment at UC Davis is among the best in the country and includes the NIH-funded Clinical and Translational Science Center (CTSC), the Career Development Core funded by the NIEHS P30 program in Environmental Health Sciences (ESH), the Center for Comparative Respiratory Biology and Medicine (CCRBM) and the Integrative Genetics and Genomics Graduate Group (IGG). The UC Davis CTSC was one of the original 12 NIH-supported Centers nationally and provides resources in bioinformatics, IRB submission and the conduct of investigator-initiated clinical trials. The EHS career development core provides vital assistance to junior investigators launching research careers including mentorship workshops, grant writing assistance and laboratory leadership-focused seminars. The CCRBM, which includes many collaborative investigators focused on pulmonary fibrosis, also offers graduate classes in clinical and advanced biostatistics. The IGG provides additional coursework in genetic epidemiology, statistical genetics and bioinformatics. Coupled with a large and well-established ILD program, UC-Davis has an established track record of excellence in patient- oriented research and provides the ideal environment in which to conduct this proposal. !