TRANSGENIC MOUSE MODELS TO STUDY THE ROLE OF NEUROTENSIN RECEPTOR

描述：这个试点项目的目标是了解 神经降压素受体(NTR)基因与酒精敏感性它已经变成了 越来越清楚的是，酒精敏感性的个体差异 由基因决定的，并可能转化为基因的成分 有酗酒倾向。多条证据表明多基因 控制对酒精的行为和药理学反应。特定的 已经确定了增加或减少的候选基因 对酒精敏感。在这些基因中，有一种是NTR，它可以调节 中枢多巴胺能功能。神经降压素的药理作用包括 体温过低，运动能力改变，止痛，肌肉松弛和 神经内分泌效应。已有研究表明，神经降压素能增强 乙醇诱导的睡眠时间和体温过低暗示NTR是一种介质 乙醇的某些作用。内源性NTR水平在 LS组小鼠脑内各区域均高于SS组小鼠。此外，最近的研究表明， NTR密度与催眠敏感性呈显著正相关 利用LSXSS RI菌株转化乙醇。始终如一地，老鼠有更高的NTR吗 与LAS相比的密度进一步表明了正遗传 酒精催眠敏感度与NTR浓度的相关性。 NTR的cDNAs已在大鼠和人中克隆和测序。我们现在在 小鼠NTR基因的测序过程。在这里，我们建议测试 假设NTR基因在酒精敏感性中起关键作用， 通过使用LSXSS RI(低水平NTR)转基因小鼠系 NTR的过度表达。LAS进一步表明正遗传 酒精催眠敏感度与NTR浓度的相关性。 NTR的cDNAs已在大鼠和人中克隆和测序。我们现在在 小鼠NTR基因的测序过程。这笔赠款的两年期 因此，我们建议： 1.完成小鼠NTR基因的序列测定。 2.利用小鼠NTR基因建立NTR(u/u)(超表达)转基因 老鼠线。 3.使用RI LSXSS和NTR(u/u)小鼠系来研究 NTR在酒精敏感性中的初始敏感性、催眠药作用 敏感度和活动能力。 这些研究将大大加深我们对非关税壁垒作为 与酒精敏感有关的遗传因素。因为高 用这些完整的小鼠进行人类和小鼠基因组研究之间的保守性 应该有助于阐明围绕着遗传差异的机制 酗酒。

DESCRIPTION: The goal of this pilot project is to understand the role of the neurotensin receptor (NTR) gene in alcohol sensitivity. It has become increasingly clear that individual differences in alcohol sensitivity are genetically determined, and may translate into components of a genetic predisposition for alcoholism. Several lines of evidence suggest polygenic control of the behavioral and pharmacologic responses to ethanol. Specific candidate genes have been identified for the increased or decreased sensitivity to alcohol. Among these genes is the NTR, known to modulate central dopaminergic function. Pharmacological effects of neurotensin include hypothermia, altered locomotor activity, analgesia, muscle relaxation and neuroendocrine effects. It has been shown that neurotensin potentiates ethanol-induced sleep time and hypothermia implicating the NTR as a mediator in some of the actions of ethanol. Endogenous NTR levels are higher in various areas of the brain of LS than SS mice. Moreover recent studies show a significant positive correlation between NTR density and hypnotic sensitivity to ethanol using LSXSS RI strains. Consistently, HAS rats have higher NTR densities compared to the LAS further indicating the positive genetic correlation between the hypnotic sensitivity to ethanol and the NTR densities. NTR cDNAs have been cloned and sequenced in rat and human. We are in the process of sequencing the mouse NTR cDNA. Here we propose to test the hypothesis that NTR gene plays a critical role in the sensitivity to alcohol, by using an LSXSS RI (with low levels of NTR) transgenic mouse line having overexpression of the NTR. LAS further indicating the positive genetic correlation between the hypnotic sensitivity to ethanol and the NTR densities. NTR cDNAs have been cloned and sequenced in rat and human. We are in the process of sequencing the mouse NTR cDNA. For the 2-year period of this grant application, we therefore propose to: 1. Complete the sequence of the mouse NTR cDNA. 2. Use the mouse NTR cDNA to develop a NTR(u/u) (ultra-expression) transgenic mouse line. 3. Use the RI LSXSS and the NTR(u/u) mouse lines to investigate the role of NTR in ethanol sensitivity by means of initial sensitivity, hypnotic sensitivity and locomotor activity. These studies will greatly enhance our understanding about the role of NTR as a genetic factor associated with alcohol sensitivity. Because of high conservation between human and mouse genome studies with these intact mice should help to elucidate the mechanisms surrounding genetic differences in alcoholism.