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，阻碍了止痛药的安全交付，特别是在儿童中。我作为一名儿科疼痛内科-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，都表明了对这个问题采取先验预防方法的必要性。这项拟议的前瞻性研究是基于我们在初步研究中观察到的吗啡引起的呼吸抑制与种族和遗传变异[三磷酸腺苷结合盒转运体(ABCB1)转运体、内源性大麻素系统(脂肪酸酰胺羟基酶/FAAH)和μ-阿片受体(OPRM1)]以及与ABCB1-FAAH相互作用更好的预测。由于MIRD的多因素性质，我设想了一种结合多种因素(遗传、 临床及其相互作用)，以提供最好的预测结果。我的长期目标是成为一名独立而有影响力的研究科学家，专注于药物基因组学在围手术期的应用，以提高儿科医疗保健的安全性和有效性。我的机构辛辛那提儿童医院(CCHMC)是美国最大的儿科医院之一，在NIH资助的研究中在儿科医疗中心中排名第二，在《美国新闻与世界报道》调查(2012)中在所有荣誉榜医院中排名第三。它拥有专门的遗传学药理学服务、最先进的研究资源和充满活力的知识氛围，为我的研究提供了一个有利的环境，加上萨迪博士在俄亥俄州立大学(OSU)的实验室的独特设施。我的导师团队包括我的主要导师，他们是NIH资助的翻译结果研究、功能药物基因组学和分子遗传学方面的经验丰富的专家，并拥有丰富的初级研究导师经验：Heubi博士，CCHMC临床和翻译科学奖(CTSA)的首席研究员(PI)，该奖项开创了新颖的翻译研究；Sadee博士，NIH/NIGMS赞助的俄亥俄州哥伦布市的XGEN项目的PI，我来自PGRN网络的导师；现场联合导师，Vinks博士，Sadhasivam博士和CCHMC的Martin，他将在药物计量学、临床药物遗传学和统计遗传学领域指导我。为促进顺利互动，制定了一项有条理的指导计划，包括每两个月访问一次俄勒冈州州立大学，与Sadee博士分享在线数据，每周与Sadee博士举行Skype会议，每周与现场导师和共同导师举行面对面会议，以及所有人定期举行视频会议。我的研究生涯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：1)药物基因组学、基因研究设计和分析，2)功能基因组学和分子遗传学，3)临床试验设计、研究伦理和生物信息学，4)有效的科学交流和拨款申请，以及5)药物动力学-药物动力学(PK-PD)分析。这项应用的科学目标，与我的长期目标一致，是识别和表征儿童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，这些因素导致了反应的变化。这一假说将通过在300名接受脊柱手术的儿童(10-18岁)中追求以下特定目标来验证：具体目标1.确定种族和性别是否会导致MIRD风险；工作假设是MIRD(临床定义：3分钟内呼吸频率为8；1；3分钟，实验定义为：低迷的二氧化碳分钟呼吸反应)在欧洲血统(使用基因组广泛关联研究阵列使用祖先信息标记进行遗传定义)和女性中风险增加。使用Logistic回归，我们将检验相关性；已知的临床预测因素，如吗啡剂量、高氧血症、疼痛评分和联合服用镇静剂将被包括为协变量。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ABCB1、FAAH和OPRM1变异及其相互作用有关。在人口分层后，将使用Logistic回归进行分析。来自目标1的重要变量将作为协变量包括在内。探索性目的：使用不一致的表型方法，探索阿片-MIRD和吗啡药代动力学(PK)途径中涉及的特定基因的变异与MIRD的关联，以最大限度地识别关联。将对吗啡浓度数据进行分析，以评估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，在翻译研究和药物基因组学方面接受交叉培训，同时促进对阿片类药物在临床实践中更安全使用的理解，并促进在儿科医疗保健情况下使用多因素预测建模。本研究的创新之处在于系统而严谨地研究了临床、新的遗传因素及其交互作用对儿童手术后同质性疼痛模型中呼吸抑制表型和吗啡PK/PD的客观和生命威胁的影响。这项拟议的研究具有重要意义，因为它有望导致变革性的、先发制人的个体化风险分层，从而指导临床决策，使吗啡更安全地使用，同时为未来竞争性的R01应用提供强有力的初步数据。这种积极主动的风险分层方法是对现状的必要背离，现状是一种不充分和反应性的临床剂量试验和错误策略。

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.