Analgesic Response to Morphine in Sickle Cell Disease

描述(申请人提供)：此职业发展奖候选人Angela Ellison博士的长期目标是开发干预措施，以改善镰状细胞病(SCD)中血管闭塞性疼痛事件(VOE)的急性管理。作为该奖项的一部分，埃里森博士将扩大她的研究培训，通过指导、有组织的实验室经验、完成相关课程、参加每周研讨会、参加全国研究会议和完成拟议的研究项目，将药物基因组学领域的技能包括在内。费城儿童医院(CHOP)为年轻科学家提供了一个出色的环境，让他们在设计和进行以患者为导向的研究时获得经验、正规指导和独立性。埃里森博士正在接受在应用基因组学、临床药理学、血液学和急诊医学方面拥有专业知识的杰出临床和基础科学家的指导。她建议的总体目标是确定SCD患者对吗啡的止痛反应个体间差异背后的药物遗传因素。该提案有四个具体目标。第一个研究是确定关键候选基因(OPRM1、COMT和UGT2B7)在非裔美国人SCD受试者中的单核苷酸多态频率和模式，并确定所发现的多态是否与种族有关。第二个目标是建立SCD儿童明确的止痛反应的临床表型。第三个目标将确定吗啡给药和由此导致的全身暴露是否与SCD儿童对吗啡的止痛反应改变有关，这些暴露由药代动力学测量确定。我们还将研究已发现的基因多态与止痛反应之间的关系。第四个目标是寻找调节或影响SCD儿童吗啡反应的其他基因。我们预计，这些研究将发现影响吗啡敏感性的基因变异，这些变异可能通过与其他遗传和/或环境因素的特定相互作用，在指导镰状细胞病VOE的药物和剂量选择方面具有预测能力。 公共卫生相关性：吗啡是治疗镰状细胞病(SCD)中严重血管闭塞性疼痛事件(VOE)的最常用处方药。在SCD中，对吗啡的镇痛反应的变化是一个众所周知但知之甚少的现象。确定与吗啡的止痛反应改变相关的遗传因素将有助于制定更好的治疗急性VOE的策略。(摘要结束)

DESCRIPTION (provided by applicant): The long-term goal of Dr. Angela Ellison, the candidate for this Career Development Award, is to develop interventions that will improve the acute management of vaso-occlusive pain events (VOE) in sickle cell disease (SCD). As part of this award, Dr. Ellison will expand her research training to include skills in the area of pharmacogenomics through mentoring, a structured laboratory experience, completion of relevant coursework, participation in weekly seminars, attendance at national research conferences and completion of the proposed research project. The Children's Hospital of Philadelphia (CHOP) provides an outstanding environment for young-scientists to gain experience, formal instruction, and independence in designing and conducting patient oriented research. Dr. Ellison is receiving mentorship from outstanding clinical and basic scientists with expertise in applied genomics, clinical pharmacology, hematology and emergency medicine. The overall goal of her proposal is to determine the pharmacogenetic factors underlying the inter-individual variation in analgesic response to morphine among patients with SCD. The proposal has four specific aims. The first is to characterize the frequency and pattern of single nucleotide polymorphisms in key candidate genes (OPRM1, COMT, and UGT2B7) among African American subjects with SCD and determine if the identified polymorphisms are associated with ethnicity. The second aim is to develop a clear clinical phenotype of analgesic response in children with SCD. The third aim will determine if morphine administration and the resulting systemic exposure, determined for individual patients by pharmacokinetic measurements, is associated with altered analgesic response to morphine in children with SCD. The relationship between the identified polymorphisms and analgesic response will also be examined. The fourth aim is an exploratory aim to identify other genes which regulate or influence morphine response in children with SCD. We anticipate that these studies will uncover genetic variants that influence morphine sensitivity and that these variants, potentially through specific interactions with other genetic and/or environment factors, will have predictive power in guiding drug and dose selection for the management of VOE in sickle cell disease. PUBLIC HEALTH RELEVANCE: Morphine is the most commonly prescribed drug for treatment of severe vaso-occlusive pain events (VOE) in sickle cell disease (SCD). Variation in analgesic response to morphine is a well known but a poorly understood phenomenon in SCD. The determination of genetic factors which are associated with altered analgesic response to morphine will aid in developing better strategies for the management of acute VOE. (End of Abstract)