Morphine Pharmacogenomics to Predict Risk of Respiratory Depression in Children

吗啡药物基因组学预测儿童呼吸抑制的风险

基本信息

批准号：
9511884
负责人：
Vidya Chidambaran
金额：
$ 13.11万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9511884
关键词：
ABCB1 gene Address Adult Adverse effects Affect Algorithms Amides Area Binding Bioinformatics CYP2D6 gene Carbon Dioxide Child Childhood Clinical Clinical Research Clinical Trials Design Clinical and Translational Science Awards Communication Comorbidity Complex Complication Data Depressed mood Development Development Plans Dose Drug Kinetics Environment Environmental air flow European Evaluation Event Fatty Acids Female Funding Future Genes Genetic Genetic study Genotype Goals Grant Healthcare Heritability Hospitals Hypoxic Brain Damage Incidence Individual Institution Intervention Laboratories Lead Life Logistic Regressions Medical Medical center Mentors Mission Mixed Function Oxygenases Molecular Genetics Morphine National Institute of General Medical Sciences Nature Ohio Operative Surgical Procedures Opioid Outcome Outcomes Research Pain Pain management Pathway interactions Patients Pediatric Hospitals Perioperative Pharmaceutical Preparations Pharmacodynamics Pharmacogenetics Pharmacogenomics Pharmacology Phenotype Physicians Physiology Population Postoperative Period Predisposition Preventive Preventive Intervention Principal Investigator Prospective Studies Public Health Race Reporting Research Research Design Research Ethics Research Personnel Resources Respiratory Failure Risk Risk Assessment Risk stratification Safety Scientist Seasons Services Site Spine surgery Structure Surveys Testing Therapeutic Index Training Translational Research Twin Studies United States National Institutes of Health Universities Validation Variant Ventilatory Depression Vertebral column Videoconferences Visit Work Writing aged base career career development clinical application clinical decision support clinical decision-making clinical effect clinical implementation clinical practice clinical predictors data sharing design endogenous cannabinoid system experience functional genomics gene interaction genetic variant genome wide association study high risk improved innovation interpatient variability laboratory experience meetings mu opioid receptors news non-genetic novel opioid therapy opioid use outcome prediction pain model pain relief pain score patient oriented research patient variability population stratification pre-clinical predictive modeling prevent public health relevance respiratory response sedative sex support tools

项目摘要

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.

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，它阻碍了安全缓解疼痛，尤其是对于儿童。我作为儿科疼痛医师 - 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这一点。拟议的前瞻性研究基于吗啡诱导的呼吸抑制 (MIRD) 与种族和遗传变异之间的密切关联[ATP 结合盒]。（ABCB1）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（OPRM1）]，以及我们在初步研究中观察到的 ABCB1-FAAH 相互作用对 MIRD 的更好预测。鉴于 MIRD 的多因素性质，我设想了一种融合多种因素（遗传、我的长期目标是成为一名独立且具有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《美国新闻与世界报道》调查（2012 年）中，该医院在 NIH 资助的研究中排名第二，在所有荣誉榜医院中排名第三。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学术氛围为我的研究提供了有利的环境，并得到了俄亥俄州立大学 (OSU) Sadee 博士实验室的独特设施的称赞。我的指导团队包括：我的主要导师是 NIH 资助的转化结果研究、功能药物基因组学和分子遗传学方面的经验丰富的专家，并且在指导初级研究人员方面拥有丰富的经验：Heubi 博士，CCHMC 的首席研究员 (PI)临床和转化科学奖 (CTSA)，它开创了新颖的转化研究，Sadee 博士是 NIH/NIGMS 赞助的俄亥俄州哥伦布 OSU 的 XGEN 项目的 PI，我来自 PGRN 网络的导师 Drs； CCHMC 的 Vinks、Sadhasivam 和 Martin 将在药物计量学、临床药物遗传学和统计遗传学领域为我提供指导，旨在促进顺利的互动。包括每两个月一次对 OSU 的访问、在线数据共享和每周与 Sadee 博士的 Skype 会议、每周与现场导师和共同导师的面对面会议以及定期的视频会议。 -关键领域的实验室培训、临床研究经验和结构化教学：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、研究伦理和生物信息学，4) 有效的科学交流和资助写作，以及 5) 药代动力学-药效 (PK-PD) 分析本申请的科学目标与我的长期目标一致，是确定儿童 MIRD 的决定因素。中心假设是，MIRD 风险是由导致反应变化的临床因素和可识别遗传因素相互作用决定的。该假设将通过在 300 名接受治疗的儿童（10-18 岁）中追求以下特定目标来检验。脊柱手术：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 风险（临床定义：呼吸频率 < 8 每分钟，持续 > 3 分钟，实验上：二氧化碳每分钟通气量反应降低）欧洲血统个体（使用全基因组关联研究阵列使用祖先信息标记进行基因定义）和女性性别中的个体增加，我们将使用逻辑回归来测试已知的临床预测因素，例如吗啡剂量、高氧血症、疼痛评分和具体目标 2. 确定特定的基因变异是否会导致 MIRD 风险；假设 MIRD 的患者间变异与特定的 ABCB1、FAAH 和 OPRM1 变异及其相互作用相关。将在群体分层后使用逻辑回归完成目标 1 中的显着变量将作为协变量包括在内：探索与 MIRD 相关的选定基因的变异的关联。将使用不一致的表型方法来分析阿片类药物-MIRD 和吗啡药代动力学 (PK) 途径，以最大限度地识别吗啡浓度数据，以评估对 PK/PD 的遗传影响。一位独立的临床科学家，接受过转化研究和药物基因组学方面的交叉培训，同时增进了对在临床实践中更安全使用阿片类药物以及在儿科医疗保健情况下使用多因素预测模型的理解。这项研究的系统性和严格性方法具有创新性。在儿科术后均质疼痛模型中研究临床、新的遗传因素及其相互作用对呼吸抑制表型和吗啡 PK/PD 的客观和生命威胁的影响，这项研究具有重要意义。导致变革性的、先发制人的个体化风险分层，可以指导临床决策以定制更安全的吗啡使用，同时为未来有竞争力的 R01 应用提供强有力的初步数据，这种主动的风险分层方法是对现状的必要偏离。这是一种不充分且反应性的反复试验临床剂量策略。