Elucidating the genomic determinants of outcomes in idiopathic pulmonary fibrosis

阐明特发性肺纤维化结果的基因组决定因素

• 批准号: 10238126
• 负责人: Justin M Oldham
• 金额: $ 7.92万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-06-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238126
• 关键词: Advisory Committees; Award; Bioinformatics; Biological; Biology; Biometry; Center Core Grants; Center for Translational Science Activities; Cessation of life; Clinical; Clinical Data; Clinical Sciences; Clinical Treatment; Clinical Trials; Clinical Trials Design; Code; Conduct Clinical Trials; Country; Coupled; Custom; DNA; Data; Data Set; Development; Development Plans; Diagnosis; Disease; Disease Outcome; Disease Progression; Early treatment; Educational workshop; Enrollment; Environment; Environmental Health; Event; Foundations; Funding; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Risk; Genomics; Genotype; Goals; Grant; Hospitalization; Individual; Institutional Review Boards; Interstitial Lung Diseases; Investigation; Laboratories; Leadership; Link; Medicine; Mentored Patient-Oriented Research Career Development Award; Mentorship; Minority; Modeling; National Institute of Environmental Health Sciences; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenetics; Phenotype; Pirfenidone; Predisposition; Prognosis; Progressive Disease; Publishing; Pulmonary Fibrosis; Registries; Research; Research Personnel; Resources; Risk; SNP array; SNP genotyping; Sampling; Single Nucleotide Polymorphism; Survival Analysis; TOLLIP gene; Technology; Testing; Therapeutic; Time; Training; United States National Institutes of Health; Writing; adverse outcome; antifibrotic treatment; antioxidant therapy; base; biobank; career; career development; clinical decision-making; clinical predictors; clinical trial enrollment; clinically relevant; cohort; comparative; design; experience; gene interaction; genetic epidemiology; genome wide association study; genome-wide; idiopathic pulmonary fibrosis; improved; laboratory experience; mortality; mortality risk; novel; patient oriented research; patient population; personalized medicine; pharmacogenetic testing; pharmacokinetics and pharmacodynamics; precision medicine; predictive modeling; programs; prospective; pulmonary function; pulmonary function decline; respiratory; response; risk stratification; side effect; skills; stem; success; therapeutic target; tool; treatment response

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. !

项目总结/摘要 特发性肺纤维化（IPF）是一种罕见但破坏性的间质性肺病，其特征是 肺功能进行性下降，诊断后中位生存期为3-5年。尽管穷人 预后，IPF遵循高度可变的临床病程，其中大多数患者经历渐进性疾病 一些人表现出相对稳定性，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IPF，但仍不清楚哪些IPF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， 我们对IPF进展和治疗反应的理解。在这一建议中，我的目的是利用 这些基因组学的进展，以确定单核苷酸多态性（SNP）与相关的IPF的结果。我 将使用从既往和当前IPF临床试验入组的患者中采集的DNA样本以及沿着 两个大型IPF登记研究。我的中心假设是病人的基因倾向于死亡，疾病 可以使用与这些终点相关的SNP前瞻性地鉴定疾病进展和治疗反应。我会 首先进行全基因组生存分析，以确定与早期IPF死亡率相关的SNP。然后我会对 相关的易感性和结果相关的SNP在几个临床试验数据集，以确定是否 他们预测相关的试验终点，包括肺功能下降和住院治疗。最后要 基因型SNP在潜在的药物遗传学基因座，以确定是否这样的SNP调节反应， 抗纤维化治疗成功完成此提案将导致定制SNP的开发 为IPF临床试验设计提供信息的芯片，具有很高的潜力来识别可能导致IPF的新基因。 日作为治疗目标。 我的长期职业目标是将遗传学纳入IPF患者的临床决策， 特别是临床试验的招募和治疗选择。为实现这一目标，相关 用于对IPF队列进行风险分层和药物遗传学检测的遗传标志物必须首先 被识别。为此，制定了一项职业发展计划，将提供出色的指导， 实验室实践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、间质性肺病和临床医学领域的领导者那里获得指导。 和翻译研究。一个由不同背景的个人组成的咨询委员会， 为临床登记和生物储存库管理提供具体指导， 实验室培训、统计遗传学和结果建模。这个K23奖项对成功至关重要 完成这份提案并及时执行我的职业发展计划，因为它将提供时间 这是实现与我的咨询委员会共同确定的现实里程碑所必需的。最终 这个奖项将使我能够成功地竞争R 01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 和翻译科学中心（CTSC），由NIEHS P30计划资助的职业发展核心 在环境健康科学（ESH），比较呼吸生物学和医学中心 （CCRBM）和整合遗传学和基因组学研究生组（IGG）。加州大学戴维斯分校的CTSC是 最初的12个NIH支持的国家中心，并提供生物信息学，IRB提交和 进行药物启动的临床试验。EHS职业发展核心提供重要帮助 初级研究人员开展研究事业，包括指导讲习班，赠款写作援助 和实验室领导力为重点的研讨会。CCRBM包括许多合作调查人员 重点是肺纤维化，也提供临床和高级生物统计学的研究生课程。的IGG 提供遗传流行病学、统计遗传学和生物信息学方面的额外课程。加上 作为一个大型且完善ILD项目，加州大学戴维斯分校在患者治疗方面有着良好的记录， 这是一个面向研究的项目，并提供了实施这一建议的理想环境。 !