Morphine Pharmacogenomics to Predict Risk of Respiratory Depression in Children

描述（由申请人提供）：阿片类药物引起的呼吸抑制是一个重要的临床问题，阻碍了疼痛缓解的安全递送，尤其是在儿童中。我作为一名儿科疼痛医生-麻醉师的临床经验，以及我在吗啡药物基因组学方面的研究背景，都指出了对这个问题进行先验预防的必要性。拟议的前瞻性研究是基于吗啡诱导的呼吸抑制（MIRD）与种族和遗传变异[ATP结合盒（ABCB 1）转运蛋白，内源性大麻素系统（脂肪酸酰胺羟化酶/FAAH）和μ-阿片受体（OPRM 1）]的稳健关联，以及我们在初步研究中观察到的MIRD与ABCB 1-FAAH相互作用的更好预测。由于MIRD的多因素性质，我设想了一种包含多个因素（遗传， 临床和它们的相互作用），以提供最佳的预测结果。我的长期目标是成为一名独立和高影响力的研究科学家，专注于药物基因组学的围手术期应用，以提高儿科医疗保健的安全性和有效性。我所在的辛辛那提儿童医院（CCHMC）是美国最大的儿科医院之一，在NIH资助的研究中排名第二，在《美国新闻与世界报道》调查（2012年）中排名第三。它拥有专门的遗传药理学服务，最先进的研究资源和充满活力的学术氛围，为我的研究提供了有利的环境，并在俄亥俄州州立大学（OSU）的Sadee博士实验室提供了独特的设施。我的指导团队包括我的主要导师，他们是NIH资助的转化成果研究，功能性药物基因组学和分子遗传学方面的经验丰富的专家，并具有指导初级研究人员的丰富经验：Heubi博士，CCHMC临床和转化科学奖（CTSA）的主要研究者（PI），该奖项开创了新颖的转化研究，Sadee博士，NIH/NIGMS在俄勒冈州立大学赞助的XGEN项目的PI，哥伦布，俄亥俄州，我的导师从PGRN网络;现场共同导师，博士文克斯，Sadhasivam和马丁在CCHMC，谁将指导我在药物计量学，临床药物遗传学和统计遗传学领域。设计了一个结构化的指导计划，以促进顺利的互动，包括每两个月访问俄勒冈州立大学，在线数据共享和每周与萨迪博士的Skype会议，每周与现场导师和共同导师面对面的会议，以及所有人之间的定期视频会议。我的研究职业发展计划涵盖了关键领域的动手实验室培训，临床研究经验和结构化教学法：1）药物基因组学，遗传研究设计和分析，2）功能基因组学和分子遗传学，3）临床试验设计，研究伦理学和生物信息学，4）有效的科学交流和资助写作，5）药代动力学-药效学（PK-PD）分析。本申请的科学目标与我的长期目标一致，是确定和表征儿童MIRD的决定因素。中心假设是MIRD的风险是由相互作用的临床和可识别的遗传因素决定的，这些因素导致反应的变化。将通过在300名接受脊柱手术的儿童（年龄10-18岁）中追求以下特定目标来检验该假设：特定目标1。确定种族和性别是否会导致MIRD风险;工作假设是< 8 per minute for >欧洲血统（使用全基因组关联研究阵列使用祖先信息标记进行遗传定义）和女性个体的MIRD（临床定义：呼吸频率&gt; 3分钟，实验定义：二氧化碳分钟通气量反应降低）风险增加。使用逻辑回归，我们将测试相关性;已知的临床预测因子，如吗啡剂量，高血氧，疼痛评分和镇静剂的联合给药将作为协变量。具体目标2。确定特定的遗传变异是否会导致MIRD风险;假设MIRD的患者间变异性与特定的ABCB 1、FAAH和OPRM 1变异及其相互作用相关。将在人群分层后使用logistic回归进行分析。目标1中的显著变量将作为协变量纳入。探索性目的：使用不一致表型方法探索与MIRD相关的阿片类药物-MIRD和吗啡药代动力学（PK）途径所涉及的选定基因变异体，以最大限度地识别相关性。将分析吗啡浓度数据，以评价对PK/PD的遗传效应。拟议研究的基本原理是，它有助于我作为一名独立的临床科学家的发展，在转化研究和药物基因组学方面进行交叉培训，同时促进对阿片类药物在临床实践中更安全使用的理解，以及在儿科医疗保健情况下使用多因素预测模型。这项研究是创新的，其系统和严格的方法，调查临床，新的遗传因素及其相互作用的影响，客观和生活中的利多卡因呼吸抑制表型，和吗啡PK/PD，在儿科手术后同质疼痛模型。拟议的研究是重要的，因为它预计将导致变革性的，先发制人的个性化风险分层，可以指导临床决策，以定制更安全的吗啡使用，同时为未来的竞争性R 01应用提供强有力的初步数据。这种积极的风险分层方法是对现状的必要偏离，现状是一种不充分和反应性的试错临床给药策略。

DESCRIPTION (provided by applicant): Respiratory depression from opioids is an important clinical problem that impedes safe delivery of pain relief especially in children. My clinical experience as a pediatric pain physician - anesthesiologist, and my research background in morphine pharmacogenomics, have both pointed to the imperative of an a priori preventive approach to this problem. The proposed prospective study is based upon robust associations for morphine induced respiratory depression (MIRD) with race and genetic variants [ATP-Binding Cassette (ABCB1) transporter, the endocannabinoid system (Fatty Acid Amide Hydroxylase/FAAH) and the μ-opioid receptor (OPRM1)], as well as better prediction of MIRD with ABCB1-FAAH interactions, that we observed in our preliminary studies. Due to the multifactorial nature of MIRD, I envision an algorithm that incorporates multiple factors (genetic, clinical and their interactions) to provide best predictive outcomes. My long-term goal is to become an independent and high impact research scientist with a focus on perioperative application of pharmacogenomics to improve the safety and efficacy of pediatric healthcare. My institution, Cincinnati Children's Hospital (CCHMC), one of the nation's largest pediatric hospitals, ranks 2nd among pediatric medical centers in NIH-funded research and 3rd among all Honor Roll hospitals in the U.S. News & World Report survey (2012). It has a dedicated Genetics Pharmacology Service, state-of-the art research resources and a vibrant intellectual ambience that provides a conducive environment for my research, complimented by the unique facilities at Dr. Sadee's laboratory at Ohio State University (OSU). My mentoring team include my primary mentors, who are NIH funded seasoned experts in translational outcomes research, functional pharmacogenomics and molecular genetics, and have extensive experience mentoring junior investigators: Dr. Heubi, CCHMC's Principal Investigator (PI) for the Clinical and Translational Science Award (CTSA), which pioneers novel translational research and Dr. Sadee, PI for the NIH/NIGMS sponsored XGEN project at OSU, Columbus, OH, my mentor from the PGRN network; on-site co-mentors, Drs. Vinks, Sadhasivam and Martin at CCHMC, who will mentor me in the areas of pharmacometrics, clinical pharmacogenetics and statistical genetics. A structured mentoring plan has been designed to facilitate smooth interactions, including bimonthly visits to OSU, online data sharing and weekly Skype meetings with Dr. Sadee, weekly face-to-face meetings with on-site mentors and co-mentors, and regular video-conferences among all. My research career development plan spans hands-on laboratory training, clinical research experience, and structured didactics in key areas: 1) Pharmacogenomics, genetic study design and analysis, 2) Functional genomics and molecular genetics, 3) Clinical trial design, research ethics and Bioinformatics, 4) Effective scientific communication and grant writing, and 5) Pharmacokinetic-Pharmacodynamic (PK-PD) analysis. The scientific objective of this application, in alignment with my long-term goal, is to identify ad characterize determinants of MIRD in children. The central hypothesis is that the risk of MIRD is determined by interacting clinical and identifiable genetic factors responsible for variations in response. The hypothesis will be tested by pursuing the following specific aims in 300 children (aged 10-18 years) undergoing spine surgery: Specific Aim 1. Determine if race and sex contribute to MIRD risk; the working hypothesis is that risk of MIRD (defined clinically: respiratory rate < 8 per minute for > 3 minutes, and experimentally: depressed carbon dioxide minute ventilation response) is increased in individuals of European descent (genetically defined using ancestry information markers using a Genome Wide Association Study array) and female sex. Using logistic regression we will test for associations; known clinical predictors like morphine doses, hyperoxemia, pain scores and co-administration of sedatives will be included as covariates. Specific Aim 2. Determine if specific genetic variants contribute to MIRD risk; the hypothesis is that inter-patient variability in MIRD is associated with specific ABCB1, FAAH and OPRM1 variants and their interactions. Analysis will be done using logistic regression after population stratification. Significant variables from Aim 1 will be included as covariates. Exploratory Aim: Explore associations with MIRD for variants in select genes involved in the opioid-MIRD and morphine pharmacokinetic (PK) pathway using a discordant phenotype approach to maximize identification of associations. Morphine concentration data will be analyzed to evaluate genetic effects on PK/PD. The rationale for the proposed research is that it facilitates my development as an independent clinician scientist, cross-trained in translational research and pharmacogenomics, while advancing the understanding of safer use of opioids in clinical practice, and the use of multifactorial predictive modeling in pediatric healthcare situations. This study is innovative in its systematic and rigorous approach in investigating the effects of clinical, novel genetic factors and their interactions, on objective and life threatenin respiratory depression phenotypes, and morphine PK/PD, in a pediatric post-surgical homogenous pain model. The proposed research is significant as it is expected to result in transformative, preemptive individualized risk stratification which can guide clinical decision making for tailored safer use of morphine, while providing strong preliminary data for a competitive R01 application in the future. This proactive approach to risk stratification is a necessary departure from the status quo, which is an inadequate and reactive trial-and-error clinical dosing strategy.