BRAIN AS TARGET FOR ANTISENSE PEPTIDE NUCLEIC ACID DRUGS

描述：(申请人摘要) 这项拟议的研究的目标是描述大鼠的 三种反义聚酰胺(“肽”)的药代动力学和药效学 针对大鼠脑中三种不同蛋白质的核酸(PNA) 神经降压素受体亚型1(NTR1)、吗啡受体亚型(MOR1)、 和5-羟色胺转运体(SERT)。这项研究的长期目标是 开发PNA作为反义和抗基因药物来治疗多种疾病， 尤其是那些影响大脑的。在不同的实验中，不同的PNA (未标记的或放射性标记的或荧光标记的 表格)将通过静脉、腹膜或口服给药给药 路线。根据一段时间内血液中PNA浓度的测量， 药代动力学变量，包括PNAS的绝对生物利用度 口头路线，将另行确定。这些PNA进入大脑的动力学 (以及其他器官)和它们在大脑中的分布也将是 由各种技术决定，包括组织学。进入的动力学 进入大脑的时间将与发病的时间进程和 从他们的行为，生理， 生物化学和分子生物学实验。行为研究将 测量抗伤害感受(NTR1和MOR1)；生理学研究，低温 (NTR1)；生化研究，NTR1、MOR1和SERT的结合位点，以及 大脑5-羟色胺及其代谢物的水平，以及分子生物学研究， 每种靶蛋白的信使核糖核酸水平。这项研究代表了最初的 可能为许多人带来可行的反义和抗基因疗法的研究 疾病的种类。

DESCRIPTION: (Applicant's Abstract) The goal of the proposed research is to characterize in rat the pharmacokinetics and pharmacodynamics of three antisense polyamide ("peptide") nucleic acids (PNAs) directed toward three different proteins in rat brain: the neurotensin receptor subtype 1 (NTR1), the morphine receptor subtype (MOR1), and the serotonin transporter (SERT). The long term goal of this research is to develop PNAs as antisense and antigene drugs to treat a variety of diseases, especially those affecting brain. In different experiments, different PNAs (either in unlabeled or in radioactively-labeled or fluorescently-labeled forms) will be administereed to rats by intravenous, intraperitoneal, or oral routes. From measurement of concentrations of PNAs in blood over time, pharmacokinetic variables, including absolute bioavailability of PNAs by the oral route, will be determined. The kinetics of entry of these PNAs into brain (as well as other organs) and their distributions within the brain will also be determined by various techniques, including histological. The kinetics of entry into brain will be correlated with the time course for the onset of and the recovery from their functional effects from behavioral, physiological, biochemical, and molecular biological experiments. Behavioral studies will measure antinociception (NTR1 and MOR1); physiological studies, hypothermia (NTR1); biochemical studies, binding sites for NTR1, MOR1, and SERT, as well as brain levels of serotonin and its metabolite, and molecular biological studies, levels of mRNA for each targeted protein. This research represents the initial studies that might lead to viable antisense and antigene therapies for many types of diseases.