Molecular mechanisms governing maintenance of neural identity

控制神经同一性维持的分子机制

• 批准号: 7536310
• 负责人: Bluma J Lesch
• 金额: $ 4.6万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-22 至 2012-07-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7536310
• 关键词: Adolescence; Adult; Affect; Attention; Binding; Biological Assay; Biological Markers; Biological Neural Networks; Biological Process; Brain; Butanones; Caenorhabditis elegans; Cell Communication; Cell Nucleus; Cell membrane; Cells; Characteristics; Chemicals; Childhood; Class; Cloning; Cognition; Communities; Complex; Contralateral; Cues; Cyclic GMP; Cytoplasm; Data; Detection; Development; Disease; Disruption; Ensure; Environment; Esthesia; Failure; Genes; Genetic; Genetic Screening; Genetic Transcription; Germ Cells; Goals; Homeodomain Proteins; Hour; Human; In Vitro; Individual; Left; Location; Maintenance; Mental disorders; Modification; Molecular; Mutation; Nematoda; Nervous System Physiology; Nervous system structure; Neurons; Nuclear Protein; Nuclear Proteins; Odors; Pathway interactions; Pattern; Phenotype; Play; Prevention; Process; Property; Proteins; Psychological reinforcement; Public Health; Regulation; Repression; Role; Role playing therapy; Schizophrenia; Sensory; Signal Transduction; Signal Transduction Pathway; Site; Specific qualifier value; Staging; Stimulus; System; Time; Transcriptional Regulation; base; cell type; extracellular; hatching; in vivo; mature animal; mutant; olfactory stimulus; programs; promoter; relating to nervous system; time interval

DESCRIPTION (provided by applicant): Precise cellular identities are necessary to maintain a coherent network of communicating neurons. In the human brain, neural networks are constructed in a well-controlled manner and then subjected to multiple iterations of reinforcement and modulation, resulting in a system capable of adult cognition. Much of this refinement takes place during childhood and adolescence, in the context of interactions with the environment. Throughout this process, specific cells establish unique identities within the network; their roles are dependent both on the initial cell type, defined by an early developmental program, and on the modifications that occur as they become integrated into the nervous system as a whole. If a neuron cannot retain its initial, fundamental characteristics as it adapts itself to the network developing around it, its role in the system may be corrupted. This study aims to examine the molecular means by which a neuron maintains crucial aspects of its identity in a changing environment. Because multiple undefined inputs to a cell may be difficult to control and their effects may be difficult to track, this study makes use of a system in which stimuli are well defined, and markers of cell identity are easy to follow. The AWC olfactory neurons in the nematode C. elegans detect a defined set of volatile chemicals and can be identified by a specific set of molecular markers. The goal of this study is to identify and characterize molecules responsible for maintaining neural identity in the AWCs after differentiation, when the neurons are first exposed to external olfactory stimuli. Specifically, this study aims to: (1) determine the mechanism of action of the nuclear protein, NSY-7, which is required for one of the AWC neurons to retain aspects of its identity after differentiation; (2) characterize the expression and regulation of the nsy-7 gene in order to better understand its function, and (3) define interactions between nsy-7 and the molecular pathway responsible for sensory signal transduction in the AWCs. Examination of the mechanisms controlling maintenance of neural identity may serve to illuminate the factors involved in certain psychiatric disorders, such as schizophrenia, that appear to be partially under genetic control but that first manifest themselves at or after adolescence. The factors responsible for the failure of an apparently normal brain to attain stability late in development remain largely unidentified, but disorders in which an seemingly stable brain departs from its normal state are widespread. Elucidation of the genes that normally control this phenomenon, and their application in the treatment and prevention of psychiatric disease, would therefore be broadly beneficial to public health and to the community.

描述（由申请人提供）：精确的细胞身份对于维持通信神经元的连贯网络是必要的。在人脑中，神经网络以良好控制的方式构建，然后经过多次迭代的强化和调制，形成一个能够进行成人认知的系统。这种改进大部分发生在童年和青少年时期，在与环境相互作用的背景下。在整个过程中，特定的小区在网络内建立唯一的身份；它们的作用既取决于由早期发育程序定义的初始细胞类型，也取决于它们融入整个神经系统时发生的修改。如果神经元在适应周围发展的网络时无法保留其初始的基本特征，那么它在系统中的作用可能会被破坏。这项研究旨在研究神经元在不断变化的环境中维持其身份的关键方面的分子手段。由于对细胞的多个未定义的输入可能难以控制，并且它们的影响也可能难以跟踪，因此本研究利用了一个系统，其中刺激被明确定义，并且细胞身份标记很容易遵循。线虫中的 AWC 嗅觉神经元可检测一组确定的挥发性化学物质，并可通过一组特定的分子标记进行识别。本研究的目的是鉴定和表征分化后（当神经元首次暴露于外部嗅觉刺激时）AWC 中负责维持神经身份的分子。具体来说，本研究的目的是：（1）确定核蛋白 NSY-7 的作用机制，该蛋白是 AWC 神经元之一在分化后保留其身份的某些方面所必需的； (2) 表征 nsy-7 基因的表达和调控，以便更好地了解其功能，(3) 定义 nsy-7 与负责 AWC 中感觉信号转导的分子途径之间的相互作用。对控制神经同一性维持的机制的检查可能有助于阐明某些精神疾病（例如精神分裂症）所涉及的因素，这些疾病似乎部分受到遗传控制，但首先在青春期或青春期后表现出来。导致表面上正常的大脑在发育后期未能达到稳定的因素在很大程度上仍不清楚，但看似稳定的大脑偏离正常状态的疾病却很普遍。因此，阐明通常控制这种现象的基因，及其在治疗和预防精神疾病中的应用，将广泛有益于公共卫生和社区。