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将通过采用主要的生化方法来表征孔戴中心“鉴定抗精神病药的细胞类型特异性作用”的主要主题，以表征据信与抗精神病药对抗精神病药作用的关键信号蛋白对抗精神病药的影响，对皮质疗法运动中神经元功能的特定方面。在AIM 1中，项目3将跟进与项目1合作进行的最新研究，这些研究发现，蛋白质Darpp-32高度富集在所有纹状体培养基神经元（MSN）中，可以通过涉及磷酸化/去磷酸化和核转运的新型机制来调节染色质功能。其他研究表明，氟哌啶醇对MSN基因表达的调节所必需的DARPP-32。项目3将阐明DARPP-32核功能在抗精神病药作用中的作用。这些研究将与Nestler博士合作进行，并将与Project 4的染色质重塑研究集成。在AIM 2中，基于与Surmeier博士（项目5）合作获得的结果，该结果显示了典型的抗精神病药氟哌啶醇对纹状体型和纹状体（MSN）（MSNS）的树突形态的特定影响，项目3将确定生物化学基础对Haloperidol观察到的影响。与项目2和5合作，这些研究将扩展到对非典型抗精神病药对MSN结构以及典型和非典型药物对皮质层状投​​射神经元的典型和非典型类别类别的生化作用的分析。在这些研究中，项目3将利用项目1和2的转化分析数据以及项目4的基因表达数据，以确定与MSN结构控制有关的候选基因。在AIM 3中，项目3将与项目2合作，以开发新方法，以利用转基因小鼠模型的功率，以允许对皮质层状电路内特定神经元细胞群体进行系统的生化和蛋白质组学分析。项目3还将为其他项目的持续研究贡献生化专业知识，并为未来的研究做出贡献，这些研究是由孔戴中心集体进行的，这是由于新发现的。