Studies of the mouse kappa opioid receptor gene

小鼠κ阿片受体基因的研究

• 批准号: 6864823
• 负责人: Li-Na Wei
• 金额: $ 12.36万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6864823
• 关键词: gene expression; genetic promoter element; genetic regulation; genetic transcription; genetically modified animals; intracellular transport; laboratory mouse; messenger RNA; neurons; neuropharmacology; opioid receptor; receptor expression; retinoate; tissue /cell culture; training

DESCRIPTION: (provided by the applicant) The purpose of this K02 application is to seek salary support for scientific career development of the PI at the Dept. Pharmacology of Univ. Minnesota Medical School. The PI was trained in molecular biology and genetics with special focus on interaction of hormone nuclear receptors and transcription factors. She has initiated a research project (DA-11190) aimed to study regulatory mechanisms for kappa opioid receptor (KOR) gene regulation. In order to develop her sceintific career along the line of drug abuse research and perform several experiments described in this project, she plans to devote more time into her research and receive further training in developmental neurobiology and opioid pharmacology. The project proposed is based upon the currently funded R01 to examine several important regulatory mechanisms underlying KOR gene expression. Three aims are proposed to address two fundamental problems in KOR gene regulation: transcription and post-transcriptional mechanisms for controlling KOR expression. Three aims are: 1)To Study Transcriptional Regulation of Mouse KOR Gene, 2) To Study Post-transcriptional Regulation of Mouse KOR Expression and 3) Transgenic Mouse Models to Study KOR Ontogeny and Regulation. The first aim will address transcriptional control by focusing on a retinoic acid (RA)-regulated silencer element located in intron 1 of the gene, and the positive mechanisms regulating promoters 1 and 2. The mechanisms underlying histone deacetylation on KOR promoters as a result of retinoid depletion will be addressed. Protein factors responsible for the activation of KOR gene in KOR neurons will be identified. An embryonic cell line P19 that is capable of differentiation into various cell lineages including KOR neurons and expresses KOR in an RA-regulated manner will be used. In the second aim, mRNA transport and protein translation efficiency will be examined in relation to the cell- and tissue type-specificity of KOR expression. The information gathered from aims 1 and 2 deals with KOR regulation in vitro. The third aim is to confirm and correct the information generated from in vitro models by using transgenic mouse models. These genetic studies will answer whether and how pharmacological problems, such as opioid addiction and tolerance, may be related to the endocrine system such as retinoid status and the homeostatic control of opioid receptor gene activity. The granting of this award will enable the PI to devote more time into her research projects and take leave of absence to receive training. This award is essential for the PI?s career development as a more productive and contributing scientist in the field of drug abuse research.

描述：（申请人提供） 该K02申请的目的是寻求科学的薪水支持 PI在大学的药理学部的职业发展。明尼苏达州 医学院。 PI接受了分子生物学和遗传学训练 特别关注激素核受体和转录的相互作用 因素。她启动了一个研究项目（DA-11190），旨在研究 Kappa阿片受体（Kor）基因调控的调节机制。为了 沿着药物滥用研究和 执行该项目中描述的几个实验，她计划投入更多 她的研究时间并接受进一步的发展培训 神经生物学和阿片类药理学。提出的项目基于 目前资助的R01检查了几种重要的调节机制 基础基因表达。提出三个目标来解决两个 KOR基因法规中的基本问题：转录和 用于控制Kor表达的转录后机制。三个目标是： 1）研究小鼠Kor基因的转录调控，2）研究 小鼠KOR表达的转录后调节和3）转基因小鼠 研究Kor个体发育和调节的模型。第一个目标将解决 转录控制通过重点放在视黄酸（RA）调节的消音器上 位于基因内含子1中的元素和调节的阳性机制 启动子1和2。基于组蛋白脱乙酰化的机制 因维生素消耗而导致的启动子将被解决。蛋白质因子 将确定负责KOR基因在KOR神经元中的激活。 能够分化为各种细胞的胚胎细胞系P19 包括KOR神经元在内的谱系和以RA调节的方式表达Kor 被使用。在第二个目标中，mRNA传输和蛋白质翻译效率 将根据KOR的细胞和组织类型特异性进行检查 表达。从目标1和2交易中收集的信息 体外调节。第三个目的是确认和纠正信息 通过使用转基因小鼠模型从体外模型产生。这些遗传 研究将回答是否以及如何以及如何使用阿片类药物等药理问题 成瘾和容忍度可能与内分泌系统有关 视网膜类似的状态和阿片受体基因活性的体内控制。 授予该奖项将使PI能够将更多时间用于她 研究项目并请假以接受培训。这个奖项是 对PI的职业发展至关重要 药物滥用研究领域的科学家。