Studies of Mouse Kappa Opioid Receptor Gene Regulation

小鼠 Kappa 阿片受体基因调控的研究

基本信息

批准号：
8127963
负责人：
Li-Na Wei
金额：
$ 37.56万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-09-30 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8127963
关键词：
3&apos Untranslated Regions Address Affect Afferent Neurons Alcohols Analgesics Animal Behavior Animals Back Biological Models Birth Brain Cells Characteristics Chromatin Cocaine Complex Coupled DNA DNA Methylation Defect Development Disease Endocytosis Esthesia Event Exhibits Fragile X Syndrome Funding Gene Expression Regulation Gene Silencing Gene Targeting Genes Genetic Genetic Programming Goals Hallucinogens Huntington Disease Kinetics Knock-out Learning Mediating Messenger RNA Methylation Modeling Molecular Genetics Mus Mutate Nervous system structure Neuromuscular Diseases Neuronal Differentiation Neurons Neurosciences Nitric Oxide Nucleic Acid Regulatory Sequences Nucleosomes Opiates Opioid Opioid Analgesics Opioid Receptor Pain Pattern Pharmaceutical Preparations Physiological Post-Transcriptional Regulation Production Protein Biosynthesis Protein Isoforms Proteins Receptor Gene Regulation Regulatory Pathway Role Second Messenger Systems Self Administration Signal Transduction Spatial Distribution Spinal Spinal Ganglia Staging Stem cells System Tissues Transcriptional Regulation Translating Translations Variant Vitamin A base chromatin remodeling density human NTN1 protein knockout animal long term memory mechanical allodynia mouse model nerve injury netrin-1 novel painful neuropathy polyglutamate promoter receptor receptor binding recombinase research study response second messenger theories transcription factor

项目摘要

DESCRIPTION (provided by applicant): Receptor binding and autoradiographic studies detected different levels of various opioid receptors (ORs) in distinct brain and spinal regions known to be involved in pain sensation or analgesic responses and genetic knockout animals provided unambiguous evidence that the three OR genes perform distinct functions. The overall goal of this project is to understand "when, where, and how much" of opioid receptor protein, specifically the kappaOR (KOR), is expressed in neurons under a physiological condition, and how is it regulated. It is hypothesized that KOR protein synthesis in neurons is regulated by a) transcriptional control that governs the birth of KOR neurons, and b) post-transcriptional control that determines when, where, and how many KOR molecules should be synthesized in neurons as needed. During the previous funding period, we carefully examined transcriptional regulation of KOR, that is primarily coupled to neuronal differentiation and includes the regulatory signals of vitamin A, nitric oxide, and the second messengers. We further uncovered several novel post-transcriptional regulatory pathways that are most relevant to the spatial control of the synthesis of KOR protein in neuronal compartments. In this renewal, we will first conduct mechanistic studies to address the novel findings of targeted KOR mRNA-transport, and its localized translational control in primary neurons. Secondly, we will extend the study of transcriptional regulatory mechanism of KOR gene by focusing on chromatin remodeling events. Thirdly, gene-targeted mouse models will be generated to address the pharmacological/physiological significance of KOR mRNA transport in neurons. We will learn: a) the genetic programming that sets the stage for KOR neurons to be born, b) the plasticity of KOR neurons to produce KOR proteins as needed, c) general and fundamental steps in neuronal gene silencing/activation at the level of chromatin remodeling, d) regulation of de novo synthesis of specific neuronal proteins in specialized neuronal compartments, and e) physiological and pharmacological relevance of localized synthesis of KOR in the context of whole animals. The potential to apply our findings and theories in the field of neuroscience, specifically the compartmentalized control of neuronal protein synthesis, can also be very significant such as in the fundamental mechanisms contributing to diseases like fragile X syndrome, neuromuscular disorders, Huntington Diseases (polyglutamate aggregates) and that implicated in long-term memory defects.

描述（由申请人提供）：受体结合和放射自显影研究在不同的大脑和脊柱区域中检测到不同水平的阿片类药物受体（ORS），已知与疼痛感觉或止痛反应有关，遗传基因敲除动物提供了明确的证据，表明三个或基因都具有不同的功能。该项目的总体目标是了解“何时，何时和多少”阿片受体蛋白，特别是Kappaor（Kor），在生理状况下在神经元中表达，如何调节它。假设神经元中的KOR蛋白合成受a）控制Kor神经元诞生的转录控制，b）转录后控制决定了何时，何处，何处和多少Kor分子应根据需要在神经元中合成。在上一个资金期间，我们仔细检查了KOR的转录调节，该调节主要与神经元分化结合，并包括维生素A，一氧化氮和第二个使者的调节信号。我们进一步发现了几种新型的转录后调节途径，这与神经元区室中Kor蛋白合成的空间控制最相关。在此续约中，我们将首先进行机械研究，以解决靶向的KOR mRNA-TRANSPORT的新发现及其在原发性神经元中的局部翻译控制。其次，我们将通过关注染色质重塑事件来扩展KOR基因的转录调节机制的研究。第三，将生成以基因为目标的小鼠模型来解决神经元中KOR mRNA转运的药理/生理意义。我们将学习：a）遗传编程为kor神经元出生的阶段，b）Kor神经元根据需要产生Kor蛋白质的可塑性，c）在染色质重塑的水平上神经元基因沉默/激活的一般和基本步骤，d）d）特定的神经元素蛋白质和蛋白质蛋白质的调节，并调节特定的神经素蛋白质和特定的蛋白质。在整个动物的背景下，Kor的局部合成的相关性。将我们的发现和理论应用于神经科学领域的潜力，特别是对神经元蛋白合成的隔室控制，也可能非常重要，例如在造成脆弱X综合征，神经肌肉疾病等疾病的基本机制中，亨廷顿疾病（亨廷顿疾病）（多状态）（多核酸盐）和多型疾病的记忆。