Characterizing the Impact of Genetic Polymorphism on Fentanyl Efficacy and Tolerance in Pediatrics

表征遗传多态性对儿科芬太尼疗效和耐受性的影响

• 批准号: 10475268
• 负责人: Kristin Nicole Grimsrud
• 金额: $ 14.63万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-10 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10475268
• 关键词: Acute Pain; Adolescent; Adult; Adverse effects; Affect; Analgesics; Anesthetics; Animal Model; Animals; Area; Award; Biology; Blood; Blood specimen; Brain; CRISPR/Cas technology; CYP2D6 gene; Child; Childhood; Chronic; Clinical; Clinical Data; Clinical Research; Code; Complex; Computer Models; Controlled Study; Cytochrome P450; Databases; Development; Discipline; Doctor of Philosophy; Dose; Drug Interactions; Drug Kinetics; Enzymes; Failure; Fentanyl; Frequencies; Funding; Gene Cluster; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; Grant; Human; Human body; Impairment; In Situ; Inflammation; Kinetics; Knock-in; Knock-out; Knowledge; Laboratory Animal Medicine; Lead; Life; Mentors; Mentorship; Metabolism; Modeling; Monitor; Mus; Mutation; Neuraxis; Opioid; Organ; Outcome; Pain; Pain management; Patient-Focused Outcomes; Patients; Pediatric Hospitals; Pediatrics; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Pharmacology; Pharmacology Study; Phenotype; Physiological; Population; Population Heterogeneity; Rattus; Renal function; Research; Research Personnel; Residencies; Risk; Role; Sampling; Sedation procedure; Special Population; Surgeon; Testing; Therapeutic; Tissues; Toxic effect; Training; Treatment Efficacy; Variant; absorption; addiction; base; career; career development; clinically relevant; cohort; demographics; drug distribution; drug efficacy; drug metabolism; drug sensitivity; enzyme activity; evidence base; genotyped patients; human model; improved; improved outcome; individual patient; inhibitor; interest; mu opioid receptors; multidisciplinary; mutant; novel; operation; opiate tolerance; opioid exposure; opioid therapy; opioid use; pain score; patient population; pediatric patients; pediatric pharmacology; pharmacodynamic biomarker; pharmacodynamic model; pharmacokinetic model; pharmacokinetics and pharmacodynamics; physiologically based pharmacokinetics; precision medicine; professor; programs; prospective; severe burns; simulation; tool; translational genetics; translational medicine

Project Summary - Kristin Grimsrud, DVM, PhD is a translational veterinary researcher and clinician whose overreaching career goal is to become an expert in pharmacogenetics and development of translational precision animal models. The research she proposes utilizes a unique pediatric burn patient human model to identify genetical polymorphisms impact on opioid metabolism and efficacy Additionally, she proposes to develop a novel rat model possessing the human variant CYP2D6*9, which is known to alter opioid metabolism. Dr. Grimsrud is an Assistant Clinical Professor and the Associate Director the Mouse Biology Program. She completed a combined DVM/PhD specializing in pharmacology and completed a residency in Laboratory Animal Medicine. The proposed career plan will build on her previous training by focusing on multidisciplinary prospective human clinical studies, advanced translational genetics, and mentorship in career development. Dr. Grimsrud has constructed a strong mentoring committee that are world experts in their disciplines. Dr. Tina Palmieri, a burn surgeon and clinical researcher, will be the primary mentor for the proposed mentoring plan. Dr. Palmieri has a Shriner’s Hospital for Children grant to evaluate genetic polymorphisms in pediatric burn patients and their associations to fentanyl efficacy. Dr. Grimsrud will lead the operations of this study for her proposed training. Together with additional secondary mentors and consultants, these experts will provide Dr. Grimsrud with the necessary guidance she needs to become an expert in human clinical research with a focus on opioids, genetics, translational animal models, as well as career development and grantsmanship. Currently little knowledge is known regarding the impact of genetic polymorphisms on fentanyl efficacy in special populations and their influence on opioid tolerance. The proposed research utilizes human and animal models to optimize fentanyl dosing in critical patients. Pediatric burn patients represent the human model due to their need for chronic opioid therapy. Repeated samples will be collected for fentanyl analysis and genotyping, along with evaluating vital parameters and pain scores for assessing efficacy. A novel translational humanized CYP2D6*9 rat model will be developed to use as a tool for pediatric pharmacology studies. Cohorts of CYP2D6*9 humanized pediatric rats will be used for chronic fentanyl administration studies to evaluate alterations in kinetics, efficacy and tolerance. Physiological based pharmacokinetic models will be developed and used for in silco analysis and extrapolation to humans to validate this model and develop an in silco simulation tool for optimizing fentanyl dosing in humans. These efforts will provide clinicians with evidence-based conclusions to guide precision dosing of opioids and provide researchers with a new animal model that can be utilized in a variety of different pharmacology studies. This award will provide Dr. Grimsrud with the necessary mentoring and research needed to start her path towards becoming a nationally-recognized independent investigator and leader in pharmacogenetics, translational and precision medicine and opioid research.

项目摘要- Kristin Grimsrud，DVM，PhD是一位翻译兽医研究员和临床医生， 超越职业目标是成为药物遗传学和翻译精度发展方面的专家 动物模型她提出的研究利用一种独特的小儿烧伤患者人体模型来识别 遗传多态性对阿片类药物代谢和疗效的影响此外，她建议开发一种新的 具有人类变体CYP 2D 6 *9的大鼠模型，已知该变体会改变阿片类药物代谢。格里姆斯鲁德博士是 临床助理教授和小鼠生物学项目副主任。她完成了一 结合DVM/博士专业药理学，并完成了在实验室动物医学住院医师。 拟议的职业计划将建立在她以前的培训，重点是多学科的未来人类 临床研究、高级转化遗传学和职业发展导师制。格里姆斯鲁德博士 建立了一个强大的指导委员会，他们是各自学科的世界专家。蒂娜·帕尔米耶里医生， 外科医生和临床研究人员将是拟议指导计划的主要指导者。帕尔米耶里医生 施里纳儿童医院拨款评估小儿烧伤患者及其 与芬太尼疗效的相关性。Dr. Grimsrud将领导本研究的操作，以进行其拟定的培训。 这些专家将与其他二级导师和顾问一起，为格里姆斯鲁德博士提供 必要的指导，她需要成为人类临床研究的专家，重点是阿片类药物，遗传学， 翻译动物模型，以及职业发展和granitarian。 目前，关于基因多态性对芬太尼疗效的影响知之甚少， 特殊人群及其对阿片类药物耐受性的影响。这项研究利用人类和动物 模型来优化芬太尼给药在危重病人。小儿烧伤患者代表人体模型， 他们对慢性阿片类药物治疗的需求将采集重复样本进行芬太尼分析和基因分型， 沿着评价生命参数和疼痛评分以评估疗效。一种新颖的翻译人性化 将开发CYP 2D 6 *9大鼠模型，用作儿科药理学研究的工具。CYP 2D 6 *9队列 人源化的幼年大鼠将用于长期芬太尼给药研究以评价动力学的改变， 有效性和耐受性。将开发基于生理学的药代动力学模型，并将其用于临床研究。 分析和外推到人类，以验证该模型，并开发一个模拟工具，以优化 芬太尼在人体内的剂量。这些努力将为临床医生提供基于证据的结论来指导 阿片类药物的精确剂量，并为研究人员提供了一种新的动物模型，可用于各种 不同的药理学研究。该奖项将为格里姆斯鲁德博士提供必要的指导和研究 需要开始她的道路，成为一个国家认可的独立调查员和领导者， 遗传药理学、转化医学和精准医学以及阿片类药物研究。