Genetic Analysis of Synaptic Function

突触功能的遗传分析

• 批准号: 7177953
• 负责人: KONRAD ERNST ZINSMAIER
• 金额: $ 7.19万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7177953
• 关键词: Affect; Antibodies; Biochemical; Biological Models; Brain; Candidate Disease Gene; Capillary Electrophoresis; Cells; Characteristics; Chemical Synapse; Chromosome Pairing; Chromosomes; Communication; Complex; DNA Sequence; Data; Defect; Development; Drosophila genus; Embryo; Epitopes; Eye; Failure; Foundations; Fractionation; Funding; Genes; Genetic; Genetic Complementation Test; Genetic Markers; Genetic Recombination; Guanosine Triphosphate Phosphohydrolases; Hand; Homologous Protein; Human; In Situ; Individuality; Knowledge; Larva; Lead; Learning; Life; Localized; Maps; Mediating; Meiosis; Meiotic Recombination; Membrane; Memory; Mental disorders; Molecular; Morphology; Muscle; Mutate; Mutation; Nature; Neurodegenerative Disorders; Neurologic; Neuromuscular Junction; Neurons; Numbers; Organism; Pathology; Pathway interactions; Pattern; Phosphorus; Process; Proteins; Regulation; Research; Resolution; Role; Signal Transduction; Site; Standards of Weights and Measures; Structure; Synapses; Synaptic Transmission; Testing; Tissues; Transgenes; Vision; concept; design; fitness; fly; genetic analysis; insight; intercellular communication; intracellular protein transport; male; millisecond; mutant; neuronal circuitry; neurotransmitter release; novel; postsynaptic; presynaptic; prevent; protein expression; protein localization location; size; synaptic function; tool; transmission process

DESCRIPTION (provided by applicant): The efficient and stable transfer of information among neurons occurs at specialized cell-cell contact sites, called synapses but neither their structure nor their strength is static. Synapses are rearranged as neuronal circuitry is refined upon changes in neuronal activity throughout life. This process is generally believed to underlie learning and memory. Failure or even subtle changes in synaptic strength and/or wiring can disturb neuronal circuits and cause neurological, psychiatric, and/or neurodegenerative disorders. However, despite considerable progress, many molecular mechanisms that govern synaptic function are still poorly understood or not known. Using the model system Drosophila, we employed a forward genetic approach and identified a large number of gene candidates that may express critical and novel synaptic components. The major questions are now: (1) Which genes have been mutated and (2) where are the underlying proteins localized within a neuron? The proposed study is designed to answer these questions for 4 of our newly identified mutations, which all affect essential presynaptic mechanisms of synaptic transmission. The gained knowledge (molecular identity and localization of the mutated proteins and their significance for synaptic function) together with the newly produced tools (transgenes and antibodies) will then provide an essential foundation to successfully obtain large-scale federal funding to dissect the mutated molecular mechanisms underlying synaptic function. Specifically, Aim 1 will physically identify the gene locus that is mutated by the synaptic mutations B332, B689, B773, and B936. This will be achieved by genetically mapping the mutation to a small number of genes, which will then allow a molecular identification of the mutation and an association of the mutation with a particular gene. Aim 2 will resolve the tissue-specific and subcellular localization of the newly identified proteins. The proposed identification and subsequent functional analysis of new components governing synaptic structure and/or function will not only advance our basic biochemical knowledge but may also yield critical insights into the pathologies of homologous proteins in human and accelerate the development of new concepts for detecting, treating, and/or preventing neurological and psychiatric disorders.

描述（由申请人提供）：神经元之间信息的有效传递发生在专门的细胞接触位点，称为突触，但它们的结构和强度都不是静态的。突触会重新排列，因为神经元回路在整个生命中的神经元活性变化中得到了完善。通常认为此过程是学习和记忆的基础。突触强度和/或接线的失败甚至细微的变化会干扰神经元电路，并导致神经系统，精神病和/或神经退行性疾病。然而，尽管取得了很大的进步，但许多控制突触功能的分子机制仍然很熟悉或尚不清楚。使用模型系统果蝇，我们采用了一种正向遗传方法，并确定了可能表达关键和新型突触成分的大量基因候选物。现在的主要问题是：（1）哪些基因已突变，以及（2）在神经元内的基本蛋白质在哪里？拟议的研究旨在为我们的4个新鉴定的突变回答这些问题，这都影响了突触传播的基本突触前机制。然后，获得的知识（突变蛋白的分子身份和定位及其对突触功能的重要性）以及新生产的工具（转基因和抗体）将为成功获得大规模的联邦资金提供基础，以解剖突变的突触功能下的突变分子机制。具体而言，AIM 1将在物理上识别突触突变B332，B689，B773和B936突变的基因基因座。这将通过将突变映射到少量基因来实现，然后将突变与特定基因的突变和缔合的分子鉴定。 AIM 2将解决新鉴定的蛋白质的组织特异性和亚细胞定位。提出的关于突触结构和/或功能的新组件的识别和随后的功能分析不仅会推进我们的基本生化知识，而且还可能会产生对人类同源蛋白质的病态的关键见解，并加快检测，治疗，治疗和/或预防神经和精神上的新概念的发展。