DEVELOPMENTAL PHARMACOLOGY OF HEPATIC OCT1

描述：（改编自申请人的描述）：肝脏代谢 以及分泌内源性和外源性物质是基本功能 胆汁是肝脏的主要排泄物， 许多药物的途径。 许多常用药物都是I型 有机阳离子胺，其通过转运体转运到肝脏中 蛋白质Oct 1 在人类中，Oct 1几乎只表达于 肝脏，进一步表明肝脏对于消除 I型有机阳离子药物。 虽然I型有机阳离子药物是 也常用于早产儿的药物 作为新生儿和儿科人群， Oct 1在正常生理学或病理生理学状态中的表达;以及 Oct 1的基因调控机制实际上仍然未被探索。 因此，本项目的目标是采用小鼠模型， 人肝组织样品以检查Oct 1的发育调节， 并确定个体发育过程中的基因调控机制， 这种重要的肝脏转运蛋白的表达。 研究人员最初将采用小鼠模型来进一步表征 小鼠肝脏I型有机阳离子摄取和表达的动力学 Oct 1在正常发育中的作用，并确定这些药物的药理作用 实验病理生理状态的变化，以及模型中的变化， 降低肝脏Oct 1表达。 他们将克隆小鼠Oct 1启动子， 采用5 '-缺失分析研究转录基因调控， 小鼠Oct 1. 随后，他们将确定基因的机制， 在正常发育和儿科疾病状态下调节人Oct 1。 最后，他们将开发出使用Oct 1启动子-报告基因的转基因小鼠。 基因构建体，以确定顺式作用调控元件， 对Oct 1的个体发育表达至关重要。 这些研究将 直接影响了我们对生理、发育 药理学和调节肝脏Oct 1转运蛋白的机制。 这些知识对于合理药理学的发展至关重要。 和治疗方法的许多有机阳离子药物用于 新生儿和儿科人群。

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.