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已知参与痛觉或镇痛反应的不同大脑和脊柱区域检测到不同水平的各种阿片受体（OR），并且基因敲除动物提供了明确的证据，证明这三个 OR 基因执行不同的功能。该项目的总体目标是了解阿片受体蛋白，特别是 kappaOR (KOR) 在生理条件下在神经元中表达的“时间、地点和程度”，以及它是如何受到调节的。据推测，神经元中的 KOR 蛋白合成受到 a) 转录控制（控制 KOR 神经元的产生）和 b) 转录后控制（决定何时、何地以及需要在神经元中合成多少 KOR 分子）的调节。在之前的资助期间，我们仔细研究了 KOR 的转录调控，它主要与神经元分化相关，包括维生素 A、一氧化氮和第二信使的调控信号。我们进一步发现了与神经元区室中 KOR 蛋白合成的空间控制最相关的几种新颖的转录后调控途径。在本次更新中，我们将首先进行机制研究，以解决靶向 KOR mRNA 转运的新发现及其在原代神经元中的局部翻译控制。其次，我们将重点关注染色质重塑事件，拓展KOR基因转录调控机制的研究。第三，将建立基因靶向小鼠模型来解决 KOR mRNA 在神经元中转运的药理学/生理学意义。我们将学习：a) 为 KOR 神经元诞生奠定基础的遗传编程，b) KOR 神经元根据需要产生 KOR 蛋白的可塑性，c) 神经元基因沉默/激活水平的一般和基本步骤染色质重塑，d) 特定神经元区室中特定神经元蛋白从头合成的调节，e) 在整个动物中局部合成 KOR 的生理学和药理学相关性。将我们的发现和理论应用于神经科学领域，特别是神经元蛋白质合成的分区控制，也可能非常重要，例如在导致脆性 X 综合征、神经肌肉疾病、亨廷顿病（聚谷氨酸聚集体）等疾病的基本机制中）并且与长期记忆缺陷有关。