Homeostatic Synaptic Depression

稳态突触抑制

• 批准号: 8333010
• 负责人: GRAEME W DAVIS
• 金额: $ 35.05万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8333010
• 关键词: Action Potentials; Alzheimer' s Disease; Biological Models; Calcium; Cells; Data; Disease; Drosophila genus; Drosophila melanogaster; Epilepsy; Genes; Goals; Grant; Human; Ion Channel; Lead; Life; Link; Mental Depression; Molecular; Mus; Muscle; Nerve; Nervous system structure; Neuronal Plasticity; Neurons; Neurophysiology - biologic function; Organism; Phosphoric Monoester Hydrolases; Phosphotransferases; Physiological; Positioning Attribute; Process; Progress Reports; Protein Kinase; Protein phosphatase; Proteins; Regulation; Role; Schizophrenia; Signal Transduction; Synapses; Synaptic Transmission; Synaptic Vesicles; Synaptic plasticity; System; Therapeutic; Vesicle; autism spectrum disorder; base; cost effective; fly; gene discovery; genetic analysis; nervous system disorder; neural circuit; neurotransmitter release; novel; presynaptic; research study; success; synaptic depression

DESCRIPTION (provided by applicant): There is increasing evidence that neural function is stabilized by homeostatic signaling systems in organisms ranging from Drosophila to mouse and human. In each example, homeostatic signaling systems were identified following an experimental perturbation of neuronal or muscle excitability. In each experiment, the cells responded to the experimental perturbation by modulating ion channel abundance or synaptic transmission to counteract the perturbation and re-establish normal activity levels. It is now widely hypothesized that defective homeostatic signaling will contribute to the cause or progression of neurological disease. However, clear links between homeostatic signaling and disease will require a detailed cellular and molecular understanding of the underlying signaling systems. Currently, the molecular basis of homeostatic signaling remains largely unknown. Over the past ten years, we have established a model system for the rapid identification and characterization of genes involved in homeostatic signaling in the nervous system of Drosophila melanogaster. Among our recent successes has been the demonstration that a schizophrenia associated gene in human, dysbindin, is critical for homeostatic signaling. In preliminary data we identified two novel proteins that control homeostatic signaling within the presynaptic nerve terminal including a novel protein kinase and protein phosphatase. We propose to characterize these new genes and define how they function during homeostatic signaling. Both genes are highly conserved in human. PUBLIC HEALTH RELEVANCE: Homeostatic signaling systems are believed stabilize neural circuitry and it is now widely believed that defective homeostatic signaling may contribute to the cause or progression of diverse neurological disorders including schizophrenia, autism-spectrum disorders, epilepsy and Alzheimer¿s. We have established a rapid, cost effective system for the discovery of genes that are involved in homeostatic signaling. Gene identification and characterization are critical steps that may ultimately lead to better therapeutics for diverse neurological diseases. !

描述（由申请人提供）：越来越多的证据表明，在从果蝇到小鼠和人类的生物体中，神经功能通过稳态信号系统稳定。在每个实施例中，在神经元或肌肉兴奋性的实验扰动之后鉴定稳态信号传导系统。在每个实验中，细胞通过调节离子通道丰度或突触传递来响应实验扰动，以抵消扰动并重新建立正常的活性水平。现在广泛假设，有缺陷的稳态信号将有助于神经系统疾病的原因或进展。然而，稳态信号和疾病之间的明确联系将需要对潜在信号系统的详细细胞和分子理解。目前，稳态信号传导的分子基础在很大程度上仍然未知。在过去的十年里，我们已经建立了一个模型系统，用于快速识别和表征果蝇神经系统中参与稳态信号转导的基因。我们最近的成功之一是证明了人类精神分裂症相关基因dysbindin对稳态信号传导至关重要。在初步的数据中，我们确定了两个新的蛋白质，控制突触前神经末梢内的稳态信号，包括一个新的蛋白激酶和蛋白磷酸酶。我们建议这些新的基因的特点，并定义它们如何在稳态信号的功能。这两个基因在人类中高度保守。 公共卫生相关性：稳态信号系统被认为稳定了神经回路，现在人们普遍认为，有缺陷的稳态信号可能有助于各种神经系统疾病的原因或进展，包括精神分裂症，自闭症谱系障碍，癫痫和阿尔茨海默氏症。我们已经建立了一个快速，成本有效的系统，发现基因参与稳态信号。基因鉴定和表征是最终可能导致更好的治疗多种疾病的关键步骤。 神经系统疾病!