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Regulation of D1 Dopamine Receptor Expression by ncRNA in Cocaine Addiction

可卡因成瘾中 ncRNA 对 D1 多巴胺受体表达的调节

基本信息

批准号：
8037925
负责人：
ELDO V KUZHIKANDATHIL
金额：
$ 14.2万
依托单位：
UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-01 至 2012-01-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8037925
关键词：
Regulation D1 Dopamine Receptor Expression

项目摘要

DESCRIPTION (provided by applicant): This competitive revision R03 application is in response to Notice Number (NOT-OD-10-032) and Notice Title: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications (R01, R03, R15, R21, R21/R33, and R37) through the NIH Basic Behavioral and Social Science Opportunity Network (OppNet). The neurotransmitter dopamine plays an important role in the brain reward process. Dysfunction of the dopaminergic system is implicated in addictive behaviors. The relationship between dopaminergic system and cocaine addiction has been well characterized. Numerous studies have shown that the D1 dopamine receptor subtype is involved in mediating the effects of cocaine. Acute and chronic administration of cocaine alters the expression levels of D1 receptors in the mesocorticolimbic pathway. The molecular mechanisms and extracellular factors that mediate the changes in D1 receptor expression in cocaine-treated animals are largely unknown; however some reports have indicated that changes occur at the post-transcriptional level. In the parent R03 project, we are testing a novel hypothesis that posttranscriptional modulation of D1 dopamine receptor expression is mediated by microRNAs that bind cis- acting elements in the 3' untranslated region (3'UTR) of the D1 receptor mRNA. The goal of the parent R03 project is to determine if cocaine-induced changes in D1 receptor expression can be related to changes in expression of a specific microRNA, and to demonstrate, using primary cultures of D1 receptor-expressing neurons, that altering the expression of this microRNA will also alter the expression of D1 receptor protein. One year into the project, we have determined that D1 receptor exhibits post transcriptional regulation in a brain region-specific manner in juvenile mice. Quantitative microRNA profiling in the caudate has identified 139 microRNAs that show a greater than 3-fold change in expression following 7 days of cocaine treatment. A subset of these microRNAs (10) show increased expression AND have putative binding sites in the D1 3'UTR, implicating them in D1 receptor posttranscriptional regulation. In this revision application, we test a new hypothesis that in mice that exhibit cocaine-induced behavior sensitization, a cocaine challenge will elicit a rapid alteration in microRNA-mediated posttranscriptional regulation of D1 receptors, increasing D1 protein expression and contributing to the increased locomotor activity. The goal of the proposed experiments is to temporally relate potential rapid changes in microRNA-mediated posttranscriptional regulation to changes in cocaine-induced locomotor behavior. The revision application meets the goals of OppNet and the Recovery Act, as it incorporates behavioral paradigms into the parent R03 project, requests funds for behavioral testing equipment and adds new personnel to assist with the behavioral experiments. The results from this project will improve our understanding of molecular mechanisms that regulate changes in dopamine receptor expression in cocaine addiction in particular, and addictive processes in general. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to determine the role of microRNAs in mediating regulation of D1 dopamine receptor expression in cocaine-induced behavior sensitization. The project will identify microRNAs that are involved in the sensitization process and determine if the levels of these microRNAs control the post- transcriptional regulation of D1 receptor expression following cocaine challenge. The results of this proposal will open a new area of research in dopamine receptor biology and lead to the development of potentially novel therapeutic methods for treating cocaine addiction.

描述（由申请人提供）：此竞争性修订 R03 申请是对通知编号 (NOT-OD-10-032) 和通知标题的回应：NIH 宣布通过 NIH 基本行为和社会科学机会网络 (OppNet) 为竞争性修订申请（R01、R03、R15、R21、R21/R33 和 R37）提供恢复法案资金。神经递质多巴胺在大脑奖励过程中起着重要作用。多巴胺能系统的功能障碍与成瘾行为有关。多巴胺能系统与可卡因成瘾之间的关系已得到很好的表征。大量研究表明，D1 多巴胺受体亚型参与介导可卡因的作用。急性和慢性服用可卡因会改变中皮质边缘通路中 D1 受体的表达水平。介导可卡因治疗动物 D1 受体表达变化的分子机制和细胞外因素在很大程度上尚不清楚；然而，一些报告表明变化发生在转录后水平。在母体 R03 项目中，我们正在测试一个新的假设，即 D1 多巴胺受体表达的转录后调节是由结合 D1 受体 mRNA 3' 非翻译区 (3'UTR) 顺式作用元件的 microRNA 介导的。母体 R03 项目的目标是确定可卡因诱导的 D1 受体表达变化是否与特定 microRNA 表达的变化有关，并使用表达 D1 受体的神经元的原代培养物证明，改变该 microRNA 的表达也会改变 D1 受体蛋白的表达。该项目进行一年后，我们确定 D1 受体在幼年小鼠中以大脑区域特异性方式表现出转录后调节。尾状核的 microRNA 定量分析已鉴定出 139 个 microRNA，在可卡因治疗 7 天后，这些 microRNA 的表达发生了超过 3 倍的变化。这些 microRNA 的一个子集 (10) 显示出表达增加，并且在 D1 3'UTR 中具有推定的结合位点，表明它们参与 D1 受体转录后调节。在本次修订申请中，我们测试了一个新假设，即在表现出可卡因诱导行为敏化的小鼠中，可卡因挑战将引起 microRNA 介导的 D1 受体转录后调节的快速改变，增加 D1 蛋白表达并有助于增加运动活性。拟议实验的目标是暂时将 microRNA 介导的转录后调节的潜在快速变化与可卡因诱导的运动行为的变化联系起来。修订版申请满足了 OppNet 和恢复法案的目标，因为它将行为范式纳入了母 R03 项目，请求资金用于行为测试设备，并增加了新人员来协助行为实验。该项目的结果将提高我们对调节可卡因成瘾中多巴胺受体表达变化的分子机制以及一般成瘾过程的理解。公共健康相关性：本提案的目标是确定 microRNA 在介导可卡因诱导的行为敏化中 D1 多巴胺受体表达调节中的作用。该项目将鉴定参与致敏过程的 microRNA，并确定这些 microRNA 的水平是否控制可卡因攻击后 D1 受体表达的转录后调节。该提案的结果将开辟多巴胺受体生物学的新研究领域，并导致开发治疗可卡因成瘾的潜在新颖治疗方法。