DEVELOPMENTAL PHARMACOLOGY OF HEPATIC OCT1

描述：(改编自申请者的描述)：肝脏代谢 内生和异生物质的分泌是必不可少的功能 肝脏的主要排泄物是肝胆分泌到胆汁 多种药理药剂的路线。许多常用药物都是I类药物 有机阳离子胺，通过转运进入肝脏 称为Oct1的蛋白质。在人类中，Oct1几乎只在 肝脏，进一步表明肝脏对于消除 第一类有机阳离子药物。尽管第一类有机阳离子药物 两种早产儿都常用的药理药物 作为新生儿和儿科人群，人们对发育情况知之甚少 Oct1在正常生理或病理生理状态下的表达；以及 Oct1基因调控的机制几乎还不清楚。 因此，该项目的目标是利用小鼠模型和 人肝组织标本检测Oct1的发育规律， 并确定了个体发生过程中的基因调控机制 这种必需的肝脏转运蛋白的表达。 研究人员将首先使用小鼠模型来进一步表征 小鼠肝脏对I型有机阳离子的摄取和表达动力学 Oct1在正常发育中的作用，并测定它们的药理作用 实验性病理生理状态的变化，以及在 降低肝脏Oct1的表达。他们将克隆小鼠Oct1启动子并 应用5‘-缺失分析方法研究人乳头瘤病毒的转录基因调控 小鼠10月1日。随后，他们将确定基因的机制 人类Oct1在正常发育和儿科疾病状态下的调节。 最后，他们将开发出使用Oct1启动子的转基因小鼠--记者 基因构建，以确定顺式作用的调控元件 对Oct1的个体表达是必不可少的。这些研究将有 直接影响我们对生理学、发育学的理解 肝脏Oct1转运蛋白的药理学和调节机制。 这些知识将对合理药理学的发展至关重要。 多种有机阳离子药物在癌症中的应用和治疗方法 新生儿和儿童人口。

DESCRIPTION: (Adapted from the applicant's Description): Hepatic metabolism and secretion of endobiotic and xenobiotic substances are essential functions of the liver, and hepatobiliary secretion into bile is the major excretory route for numerous pharmacologic agents. Many commonly used drugs are Type I organic cation amines, which are transported into the liver via a transport protein termed Oct1. In humans, Oct1 is expressed almost exclusively in the liver, further indicating the importance of the liver for the elimination of Type I organic cationic drugs. Although Type I organic cationic drugs are pharmacologic agents that are commonly used in both premature infants as well as neonatal and pediatric populations, little is known about the developmental expression of Oct1 in normal physiology or in pathophysiological states; and the mechanisms of gene regulation of Oct1 remain virtually unexplored. Therefore, the objectives of this project are to employ murine models and human liver tissue samples to examine the developmental regulation of Oct1, and determine the mechanisms of gene regulation during the ontogenic expression of this essential hepatic transporter. The investigators will initially employ murine models to further characterize the kinetics of hepatic Type I organic cation uptake and expression of mouse Oct1 in normal development, and determine the pharmacologic effect of these changes in experimental pathophysiological states, as well as in models with reduced hepatic Oct1 expression. They will clone the mouse Oct1 promoter and employ 5'-deletional analysis to study the transcriptional gene regulation of murine Oct1. Subsequently they will determine the mechanisms of gene regulation of human Oct1 in normal development and pediatric disease states. Finally, they will develop transgenic mice that employ Oct1 promoter-reporter gene constructs to determine the cis-acting regulatory elements that are essential for the ontogenic expression of Oct1. These studies will have direct implications on our understanding of the physiology, developmental pharmacology, and mechanisms of regulation of the hepatic Oct1 transporter. This knowledge will be critical for the development of rational pharmacologic and therapeutic approaches of the many organic cationic drugs used in the neonatal and pediatric population.