CHARACTERIZATION OF A UGT FOR MORPHINE 6 GLUCURONIDE

描述：(申请人摘要) 申请者的长期目标是成为一名内科科学家。 具有新生儿药理学方面的专业知识。为了实现这一目标，她有 组建了一个由生理学和医学系的导师组成的团队 俄勒冈州健康科学的药理学和儿科系 大学(OHSU)，由以下人员组成：一名在 药物滥用领域和吗啡代谢；熟练的儿科医生 最新的分子和基因技术；是专家的药理学家 蛋白质化学和药物代谢；以及分子内分泌学家 在分子生物学方面有20多年的经验。此外，OHSU 为申请者提供一个强大的研究环境，使其能够继续深造 目标。这项研究项目的总体目标是描述一只几内亚人的特征。 猪UDP-葡萄糖醛酸基转移酶(UGT)将吗啡代谢为 吗啡-6-葡萄糖醛酸苷，其活性代谢物。这种代谢物会产生 被人类、豚鼠和兔子发现，但不被更频繁研究的人发现 老鼠。有相当多的证据表明，生产的UGT 吗啡-6-葡萄糖醛酸不同于那些产生 非止痛性代谢物，吗啡-3-葡萄糖醛酸苷。这部剧的特点将是 包括蛋白质的纯化、cDNAs的鉴定以及 本病的个体发生和组织分布的阐明 葡萄糖醛酸基转移酶。由此产生的吗啡-6-葡萄糖醛酸苷 转移酶是一种更有效的止痛剂和呼吸抑制药 亲生吗啡。因此，在药物滥用领域，重要的是 了解本病的组织分布和个体发育 葡萄糖醛酸基转移酶。在为以下目标作出贡献的过程中 对吗啡代谢的了解，调查者将获得一个 多维度的教育，使她成为一个独立的 具有临床和医学专业知识的新生儿药理学研究人员 基础研究。

DESCRIPTION: (Applicant's Abstract) The long-term objective of the applicant is to become a physician-scientist with expertise in Neonatal Pharmacology. To achieve that goal she has assembled a team of mentors from the Departments of Physiology and Pharmacology and the Department of Pediatrics at Oregon Health Sciences University (OHSU) that consists of: a Pharmacologist with expertise in the drug abuse field and morphine metabolism; a Pediatrician skilled in the latest molecular and genetic techniques; a Pharmacologist who is an expert in protein chemistry and drug metabolism; and a Molecular Endocrinologist with over 20 years experience in molecular biology. In addition, OHSU provides a strong research environment in which the applicant can pursue her goals. The overall goal of the research project is to characterize a guinea pig UDP-glucuronosyltransferase (UGT) that metabolizes morphine to morphine-6-glucuronide, its active metabolite. This metabolite is produced by humans, guinea pigs and rabbits, but not by the more frequently-studied rat. There is considerable evidence that the UGT that produces morphine-6-glucuronide is different from those that produce the non-analgesic metabolite, morphine-3-glucuronide. The characterization will consist of purification of the protein, identification of the cDNA, and elucidation of the ontogeny and tissue distribution of this glucuronosyltransferase. The morphine-6-glucuronide produced by this transferase is a more potent analgesic and respiratory depressant than the parent morphine. It is, therefore, important in the drug abuse field to understand the tissue distribution and ontogeny of this glucuronosyltransferase. In the process of contributing to the understanding of morphine metabolism, the investigator will acquire a multidimensional education that will allow her to function as an independent investigator in neonatal pharmacology with expertise in both clinical and basic research.