Analgesic Response to Morphine in Sickle Cell Disease

描述（由申请人提供）：本次职业发展奖候选人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）患者血管闭塞性疼痛事件（VOE）的急性管理。作为该奖项的一部分，埃里森博士将通过指导、结构化实验室经验、完成相关课程、参加每周研讨会、参加国家研究会议和完成拟议的研究项目，扩大她的研究培训，包括药物基因组学领域的技能。费城儿童医院（CHOP）为年轻科学家在设计和开展以患者为导向的研究方面获得经验、正式指导和独立提供了良好的环境。Ellison博士在应用基因组学、临床药理学、血液学和急诊医学领域获得杰出的临床和基础科学家的指导。她建议的总体目标是确定SCD患者对吗啡镇痛反应的个体差异背后的药物遗传因素。该提案有四个具体目标。首先，研究非裔美国SCD患者关键候选基因（OPRM1、COMT和UGT2B7）单核苷酸多态性的频率和模式，并确定这些多态性是否与种族有关。第二个目的是开发一个明确的临床表型镇痛反应的儿童SCD。第三个目的是确定吗啡给药和由此产生的全身暴露（通过药代动力学测量确定个体患者）是否与SCD儿童对吗啡的镇痛反应改变有关。鉴定的多态性和镇痛反应之间的关系也将被检查。第四个目的是一个探索性的目的，以确定其他基因调节或影响吗啡反应的儿童SCD。我们预计这些研究将揭示影响吗啡敏感性的遗传变异，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管理的药物和剂量选择方面具有预测能力。

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.