Studies of the Mouse Kappa Opioid Receptor Gene

小鼠 Kappa 阿片受体基因的研究

• 批准号: 7190873
• 负责人: Li-Na Wei
• 金额: $ 12.87万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7190873
• 关键词: 3' Untranslated Regions; Address; Affect; Amino Acid Sequence; Analgesics; Animal Model; Animals; Award; Biological Process; Cells; Chromatin; Condition; Coupled; Development; Drug Receptors; Drug abuse; Elements; Endocrine system; Event; Gene Expression; Genes; Genetic; Genetic Programming; Genetic Transcription; Homeostasis; Independent Scientist Award; Intervention; Investigation; Knock-out; Light; Messenger RNA; Molecular; Mus; National Institute of Drug Abuse; Nervous system structure; Neurologic; Neurons; Opioid; Opioid Receptor; Paper; Peptide Sequence Determination; Pharmaceutical Preparations; Physiological; Physiology; Post-Transcriptional Regulation; Production; Promoter Regions; Proteins; Publishing; Rate; Receptor Gene; Regulation; Regulator Genes; Research; Research Project Grants; Scientist; Specificity; Staging; Time; Transcriptional Regulation; Transgenic Organisms; Translations; Work; addiction; animal tissue; base; career; chromatin remodeling; kappa opioid receptors; mature animal; mouse model; prenatal; protein expression; receptor; receptor expression; response; transcription factor

DESCRIPTION (provided by applicant): This application is for a renewal of a NIDA sponsored K02 (DA13926) Independent Scientist Award. The current K02 award (2002-2007) allowed the PI to develop her independent research career that focuses on genetic programming for the expression of drug receptors, in particular, the opioid receptors. It is known that the amounts of opioid receptors are crucial for the analgesic effects of opioid compounds. The control is through genetic programming that instructs the cells to express these genes properly and specifically (transcriptional control) and to produce these proteins from mRNAs (post-transcriptionally) according to the needs. In the previous studies, the major task was to dissect the basic elements responsible for transcriptional and post-transcriptional regulation of opioid receptor genes, that include determining DMA sequences and protein factors required for transcriptional control, identification of post-transcriptional events that modulate the rate, the place and the time of opioid receptor protein production in neurons, and dissecting fundamentally important mechanisms in their regulation. Over the period of 2002-2005 supported by this K02, the Pi's works were published in 35 papers. The renewal proposal will continue systemic investigation into the mechanistic basis of these biological processes and the integration in the animals for understanding the homeostatic control of opioid receptor expression. Thus, the overall direction of the research project remains the same. Specific aims are: 1) to extend studies of transcriptional regulation of KOR gene by focusing on how transcription factors interact with chromatin of the KOR gene, leading to chromatin remodeling of the promoter regions; 2) to identify post-transcriptional events that regulate KOR protein production in neurons by focusing on the control of mRNA transport and local translation in neurons regulated by the 5'- and the 3'-untranslated regions; and 3) to produce transgenic mouse models to answer whether and how these regulatory events affect the manifestation of pharmacological effects and problems of opioids, such as addiction and tolerance. These studies are clinically important for the identification of crucial steps in genetic programming of opioid receptor expression that may shed light on potential targets of interventions for drug abuse problems, and are fundamentally applicable for the understanding of critical biological processes required for neuronal compartment-specific expression of proteins that are of significant pharmacological and neurological consequences. This award is also essential for the Pi's continual career development as an independent scientist in the field of drug abuse research.

描述（由申请人提供）：此申请是为了续签NIDA赞助的K02（DA13926）独立科学家奖。当前的K02奖（2002-2007）允许PI发展她的独立研究职业，该研究重点是用于表达药物受体的基因编程，特别是阿片类药物受体。众所周知，阿片受体的量对于阿片化合物的镇痛作用至关重要。控制是通过遗传编程来指示细胞正确，具体地（转录对照）表达这些基因，并根据需求从mRNA（转录后）产生这些蛋白质。在先前的研究中，主要任务是解剖阿片类药物受体基因的转录和转录后调节的基本要素，其中包括确定转录控制所需的DMA序列和蛋白质因素，鉴定后的转录后事件，这些事件鉴定了调节速度，速度和时间生产的速度和时间的神经元中的速度和时间的均和分化的机制。在该K02支持的2002 - 2005年期间，PI的作品发表在35篇论文中。续签建议将继续进行全身研究，以对这些生物学过程的机械基础以及动物的整合，以理解阿片类受体表达的稳态控制。因此，研究项目的总体方向保持不变。具体目的是：1）通过关注转录因子如何与KOR基因的染色质相互作用，从而扩展Kor基因转录调节的研究，从而导致启动子区域的染色质重塑； 2）通过关注由5'-和3'非翻译区域调节的神经元中的mRNA转运和局部翻译来确定调节神经元中Kor蛋白质产生的转录事件； 3）产生转基因小鼠模型，以回答这些调节事件是否以及如何影响阿片类药物（例如成瘾和耐受）的药理学作用和问题的表现。这些研究对于鉴定阿片类药物受体表达的遗传编程的关键步骤在临床上很重要，这可能揭示了药物滥用问题的潜在干预措施的潜在靶标，并且从根本上适用于理解对神经元阶层特异性蛋白质所需的关键生物学过程，这些蛋白质是显着的药理和神经学后果。该奖项对于PI作为药物滥用研究领域的独立科学家的持续职业发展也是必不可少的。