P2 - Role of mGluR5/CK1-CK2/DARPP-32 Pathway in Psychostimulant Effects

P2 - mGluR5/CK1-CK2/DARPP-32 通路在精神兴奋作用中的作用

• 批准号: 8334266
• 负责人: PAUL GREENGARD
• 金额: $ 32.58万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8334266
• 关键词: Address; Attention; Attention deficit hyperactivity disorder; Behavior; Behavioral; Biochemical; Brain; CSNK1A1 gene; Cell Nucleus; Characteristics; Cocaine; Complement; Corpus striatum structure; Cytokeratin-18 Staining Method; Cytosol; DARPP; Dendritic Spines; Development; Dopamine; Dopamine D2 Receptor; Dopamine Receptor; Event; Functional disorder; G Protein-Coupled Receptor Genes; Glutamates; Impulsivity; In Vitro; Instruction; Knock-out; Knowledge; Light; Link; Measures; Mediating; Metabotropic Glutamate Receptors; Molecular; Morphology; Mus; Neurons; Neurotransmitters; Nuclear; Pathway interactions; Pharmaceutical Preparations; Phosphoproteins; Phosphorylation; Phosphotransferases; Physiological; Play; Population; Program Research Project Grants; Protein Kinase; Protein phosphatase; Proteins; Proteomics; Regulation; Relative (related person); Research; Role; Signal Pathway; Signal Transduction; Technology; Therapeutic; Time; Ubiquitination; Vertebral column; Work; casein kinase; drug of abuse; in vivo; novel; overexpression; psychostimulant; receptor; response; small molecule; trafficking

It is well established that DARPP-32 is a key integrator of striatal signaling in physiological conditions as well as in the context of psychostimulants. Beside dopamine, various neurotransmitters such as glutamate act on and modify DARPP-32 downstream signaling. Our studies have demonstrated the importance of multiple signaling pathways converging on DARPP-32 in the action of drugs of abuse, and recently we have developed state-of-the-art technologies proving that these signaling events are specifically regulated in different sub-populations of medium spiny neurons (MSNs) that differentially express Dl and D2 types of dopamine receptor. Our ongoing research will focus on studies of mGluRS, an important GPCR invovled in glutamate-dependent DARPP-32 regulation, and two kinases, CKI and CK2. CKI is a crucial player in the mGluR5/DARPP-32 pathway and CK2 is essential for regulation of DARPP-32 nuclear trafficking. We have generated novel mouse lines for each of the three proposed Aims that will allow us not only to study the impact of psychostimulants in vivo but also to evaluate the relative importance of D1- and D2-MSNs in these phenomena. To address these questions we propose three Aims in Project 2 of the Program Project Grant. In Aim I we will study the role of the newly discovered mGluRS regulator Norbin in the actions of psychostimulants. In Aim II we will study the role of CK1 in the mGluRS/DARPP-32 pathway in vivo. We will also further charcterize the CK16 over expressing mice that present some behavioral features that ressembles ADHD. We will further address differences observed between Dl and D2 receptor pathways. In Aim III we will study the role of CK2 in the actions of psychostimulants, in both Dl and D2-MSNs using specific KO strategies. Results from this Project will complement the other two Projects of this Program Project grant. In addition we will also carry out a number of collaborative studies with Projects 1 and 3, including studies involving spine morphology with Project 1 and phosphoproteomic studies and behavioral studies with Project 3.

已经确定DARPP-32是生理条件下以及精神兴奋剂背景下纹状体信号传导的关键整合剂。除了多巴胺，各种神经递质如谷氨酸作用于并改变DARPP-32下游信号传导。我们的研究已经证明了在滥用药物的作用中汇聚在DARPP-32上的多种信号传导途径的重要性，并且最近我们已经开发了最先进的技术，证明这些信号传导事件在差异表达D1和D2型多巴胺受体的中型多刺神经元（MSN）的不同亚群中被特异性调节。我们正在进行的研究将集中在mGluRS，一个重要的GPCR参与谷氨酸依赖性DARPP-32的调节，和两个激酶，CKI和CK 2的研究。CKI是mGluR 5/DARPP-32通路中的关键参与者，CK 2是调节DARPP-32核运输所必需的。我们已经产生了新的小鼠品系的三个拟议的目标，这将使我们不仅能够研究在体内的精神兴奋剂的影响，但也评估的D1和D2-MSN在这些现象的相对重要性。为了解决这些问题，我们在项目2中提出了三个目标。 在目的我，我们将研究新发现的mGluRS调节Norbin在精神兴奋剂的行动中的作用。在目的II中，我们将研究CK 1在体内mGluRS/DARPP-32通路中的作用。我们还将进一步表征CK 16过表达小鼠，这些小鼠表现出一些类似ADHD的行为特征。我们将进一步阐述在D1和D2受体途径之间观察到的差异。在目的III中，我们将使用特定KO策略在D1和D2-MSN中研究CK 2在精神兴奋剂作用中的作用。该项目的成果将补充该项目赠款的其他两个项目。此外，我们还将与项目1和项目3开展一些合作研究，包括项目1的脊柱形态学研究和项目3的磷酸蛋白质组学研究和行为研究。