Biochemical Mechanisms Mediating Cell Type-Specific Actions of Antipsychotic Drug

介导抗精神病药物的细胞类型特异性作用的生化机制

• 批准号: 8150123
• 负责人: ANGUS C. NAIRN
• 金额: $ 27.72万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8150123
• 关键词: Address; Affect; Antipsychotic Agents; Biochemical; Candidate Disease Gene; Cells; Chromatin; Collaborations; Corpus striatum structure; Data; Development; Future; Gene Expression; Haloperidol; Mediating; Mental disorders; Methods; Morphology; Neurons; Nuclear; Nuclear Translocation; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Population; Protein Dephosphorylation; Proteins; Proteomics; Public Health; Regulation; Role; Schizophrenia; Signal Transduction; Signaling Protein; Structure; Transgenic Mice; Work; atypical antipsychotic; base; cell type; chromatin remodeling; follow-up; mouse model; novel; novel therapeutics

Project 3 will address the major theme of the Conte center "Identification of cell type-specific actions of antipsychotic drugs" by taking primarily biochemical approaches to characterize key signaling proteins believed to be involved in the effects of antipsychotic drugs on specific aspects of neuronal function within corticostriatal circuits. In Aim 1, Project 3 will follow up from recent studies carried out in collaboration with Project 1 that have found that the protein DARPP-32, which is highly enriched in all striatal medium spiny neurons (MSNs), regulates chromatin function through a novel mechanism involving phosphorylation/dephosphorylation and nuclear translocation. Other studies indicate that DARPP-32 is required for the effects of haloperidol on regulation of MSN gene expression. Project 3 will elucidate the role of DARPP-32's nuclear function in the actions of antipsychotic drugs. These studies will be carried out in collaboration with Dr. Nestler, and will be integrated with Project 4's studies of chromatin remodeling. In Aim 2, building on results obtained in collaboration with Dr. Surmeier (Project 5) that show specific effects of the typical antipsychotic haloperidol on the dendritic morphology of striatonigral and striatopallidal (MSNs), Project 3 will identify the biochemical basis for the observed effects of haloperidol. In collaboration with Projects 2 and 5, these studies will be expanded to analysis of the biochemical effects of atypical antipsychotic drugs on the structure of MSNs, as well as of both typical and atypical classes of drug on corticostriatal projection neurons. In these studies, Project 3 will make use of translational profiling data from Projects 1 and 2, as well as gene expression data from Project 4, to identify candidate genes involved in control of MSN structure. In Aim 3, Project 3 will work together with Project 2 in the development of new methods to exploit the power of transgenic mouse models to allow for systematic biochemical and proteomic analysis of specific neuronal cell populations within corticostriatal circuits. Project 3 will also contribute biochemical expertise to ongoing studies by the other projects, as well as contribute to future studies that are carried out collectively by the Conte Center as a result of new discoveries made.

项目3将通过主要采用生物化学方法来表征被认为参与抗精神病药物对皮质纹状体回路内神经元功能特定方面的影响的关键信号蛋白，来解决Conte中心的主题“抗精神病药物的细胞类型特异性作用的鉴定”。在目标1中，项目3将跟进最近与项目1合作进行的研究，这些研究发现，在所有纹状体中型棘神经元（MSN）中高度富集的蛋白质DARPP-32通过涉及磷酸化/去磷酸化和核转位的新机制调节染色质功能。其他研究表明，DARPP-32是氟哌啶醇调节MSN基因表达所必需的。项目3将阐明DARPP-32的核功能在抗精神病药物作用中的作用。这些研究将与Nestler博士合作进行，并将与项目4的染色质重塑研究相结合。在目标2中，基于与Surmeier博士（项目5）合作获得的结果，该结果显示典型抗精神病药物氟哌啶醇对纹状体黑质和纹状体苍白（MSN）树突形态的特定影响，项目3将确定氟哌啶醇观察到的影响的生化基础。与项目2和5合作，这些研究将扩展到分析非典型抗精神病药物对MSN结构的生化作用，以及典型和非典型药物对皮质纹状体投射神经元的生化作用。在这些研究中，项目3将利用项目1和2的翻译谱数据，以及项目4的基因表达数据，以确定参与控制MSN结构的候选基因。在目标3中，项目3将与项目2合作开发新方法，利用转基因小鼠模型的能力，对皮质纹状体回路内的特定神经元细胞群进行系统的生化和蛋白质组学分析。项目3还将为其他项目正在进行的研究提供生物化学专业知识，并为康特中心因新发现而集体开展的未来研究做出贡献。