TRANSGENIC MOUSE MODELS TO STUDY THE ROLE OF NEUROTENSIN RECEPTOR

转基因小鼠模型研究神经降压素受体的作用

• 批准号: 6563127
• 负责人: Robert A Harris
• 金额: $ 18.46万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-01 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6563127
• 关键词: alcoholism /alcohol abuse; animal genetic material tag; behavioral /social science research tag; complementary DNA; disease /disorder model; genetically modified animals; hormone receptor; laboratory mouse; model design /development; neurotensin; nucleic acid sequence; protein structure function; psychopharmacology

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.

描述：该试点项目的目标是了解 神经降压素受体（NTR）基因与酒精敏感性有关。它已经成为 越来越明显的是，酒精敏感性的个体差异 基因决定的，并且可以转化为遗传的组成部分 酗酒的倾向。多项证据表明多基因 控制对乙醇的行为和药理学反应。具体的 已鉴定出增加或减少的候选基因 对酒精的敏感性。这些基因中有一个 NTR，已知它可以调节 中枢多巴胺能功能。神经降压素的药理作用包括 体温过低、运动活动改变、镇痛、肌肉松弛和 神经内分泌作用。研究表明，神经降压素可增强 乙醇诱导的睡眠时间和体温过低表明 NTR 作为调节因子 乙醇的一些作用。内源性 NTR 水平较高 LS小鼠大脑的各个区域均优于SS小鼠。此外，最近的研究表明 NTR密度与催眠敏感性之间显着正相关 使用 LSXSS RI 菌株将其转化为乙醇。一致地，HAS 大鼠具有更高的 NTR 与 LAS 相比的密度进一步表明阳性遗传 对乙醇的催眠敏感性与 NTR 密度之间的相关性。 NTR cDNA 已在大鼠和人类体内进行克隆和测序。我们在 对小鼠 NTR cDNA 进行测序的过程。这里我们建议测试一下 假设NTR基因在对酒精的敏感性中起着关键作用， 通过使用具有低水平 NTR 的 LSXSS RI 转基因小鼠品系 NTR 的过度表达。 LAS进一步表明阳性遗传 对乙醇的催眠敏感性与 NTR 密度之间的相关性。 NTR cDNA 已在大鼠和人类体内进行克隆和测序。我们在 对小鼠 NTR cDNA 进行测序的过程。本补助金期限为 2 年 申请，因此我们建议： 1. 完成小鼠 NTR cDNA 的序列。 2. 使用小鼠NTR cDNA开发NTR(u/u)（超表达）转基因 鼠标线。 3. 使用 RI LSXSS 和 NTR(u/u) 小鼠系来研究 NTR 在乙醇敏感性中通过初始敏感性、催眠 敏感性和运动活动。 这些研究将极大地增强我们对 NTR 作用的理解 与酒精敏感性相关的遗传因素。因为高 用这些完整的小鼠研究人类和小鼠基因组之间的保守性 应该有助于阐明围绕遗传差异的机制 酗酒。