A transgenic platform to produce genetic tools for monitoring & manipulating plas

生产用于监测的遗传工具的转基因平台

• 批准号: 8139694
• 负责人: Hongkui Zeng
• 金额: $ 44.41万
• 依托单位: ALLEN INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8139694
• 关键词: Address; Animal Testing; Animals; Area; Behavior; Biological Neural Networks; Brain; Brain Diseases; Breeding; Calcium; Cells; Collaborations; Commit; Communities; DLG4 gene; Databases; Development; Diphtheria Toxin; Disease; ES Cell Line; Excision; Farming environment; Functional Imaging; GABA transporter; Gene Expression; Gene Targeting; Generations; Genes; Genetic; Genome; Genomics; Glutamates; Halorhodopsins; Health; Image; Individual; Institutes; Interneurons; Knowledge; Label; Light; Location; Measures; Mediating; Mental Health; Methods; Molecular; Monitor; Mus; Neuronal Plasticity; Neurons; Neurosciences; Neurosciences Research; Physiology; Plastics; Play; Population; Process; Proteins; Public Health; Reporter Genes; Research; Research Personnel; Resolution; Resources; Role; Synapses; Technology; Testing; Time; Toxin; Transgenic Animals; Transgenic Mice; Transgenic Organisms; United States National Institutes of Health; calcium indicator; cell type; design and construction; excitatory neuron; genetic manipulation; gephyrin; improved; inhibitory neuron; innovative technologies; neural circuit; neuronal circuitry; postsynaptic; presynaptic; programs; receptor; recombinase; response; skills; tool; voltage

DESCRIPTION (provided by applicant): The use of transgenic tools to selectively label and detect individual neuronal populations and modulate gene expression in those cells to manipulate activity can have significant impact in neuroplasticity research. In recent years a number of molecular tools have been developed to study neural circuitry and plasticity at exquisite detail and control. However, application of these tools in different neuronal cell types and circuits at cellular and subcellular level has been limited, in particular because of the time and effort needed to develop each individual transgenic animal. This issue has been partially addressed by putting in great effort into the development of cell type specific Cre-driver lines. However, there have still been hurdles to overcome in creating the necessary numbers of Cre responsive transgenic lines that can express the molecular tools at sufficiently strong levels for imaging and for functional manipulation in a cell type specific, subcellularly targeted manner for use by academic researchers. To attempt to address this issue, we propose to systematically target a set of genomic loci that will convey strong ubiquitous expression or selective pre and post-synaptic specific targeting of genes in inhibitory and excitatory neurons respectively, to develop a Cre-responder platform in these genomic loci to which any existing or newly developed molecular tools can be easily inserted. We are committed to use this program to provide diverse transgenic mice to the academic community that will exploit many of the new tools and probes to study neural networks and in particular study neuronal plasticity as it relates to behavior and physiology. The Allen Institute has a high throughput ISH platform and capability of high resolution image acquisition and data-basing. By combining these innovative technologies with the transgenic lines to be developed, we will be able to increase the utility of the transgenic mice as an approach to study neuroplasticity by making such experimental animals freely available for the neuroscience community. PUBLIC HEALTH RELEVANCE: Neuroplasticity is a fundamental process underlying brain development and brain's ability to acquire knowledge and skills, as well as a component of many brain disorders. Genetic tools have been widely used in every area of plasticity research. Our proposed research will provide to the neuroscience community a transgenic platform to incorporate state-of-the-art probes and tools for monitoring and manipulating plasticity at cellular and subcellular levels. Use of these genetic tools by the neuroscience community will have major impact on the further understanding of the roles of plasticity plays in brain function and diseases, leading to ways in treating diseases and improving public health.

描述（由申请人提供）：使用转基因工具选择性标记和检测单个神经元群体并调节这些细胞中的基因表达来操纵活性，对神经可塑性研究有重大影响。近年来，已经开发了许多分子工具来研究神经回路和可塑性，以精美的细节和控制。但是，这些工具在细胞和亚细胞水平的不同神经元细胞类型和电路中的应用受到限制，尤其是由于开发每个单个转基因动物所需的时间和精力。通过在特定细胞类型的特定CRE驱动器线的开发中付出了巨大的努力来部分解决这个问题。但是，在创建必要数量的CRE响应转基因线上，仍然存在障碍，这些线路可以在足够强的水平上表达分子工具，以进行成像和功能操纵，以特定于细胞类型的特定于细胞类型的，细胞细胞的靶向方式，以供学术研究人员使用。为了解决这个问题，我们建议系统地针对一组基因组基因座，这些基因素基因座将分别传达出强大的无处不在的表达或选择性的前和突触后特异性靶向抑制性和兴奋性神经元中基因的特异性靶向，以在这些现有或新开发的分子工具中可以在这些基因组中开发Cre-Responder平台。我们致力于使用该计划为学术界提供多种转基因小鼠，这些小鼠将利用许多新工具和探针来研究神经网络，特别是研究与行为和生理学有关的神经元可塑性。艾伦学院（Allen Institute）具有高吞吐量的ISH平台，以及高分辨率图像采集和数据基础的能力。通过将这些创新技术与要开发的转基因线相结合，我们将能够通过使这种实验性动物自由地用于神经科学界，将转基因小鼠的效用作为研究神经可塑性的方法。公共卫生相关性：神经可塑性是大脑发育和大脑获得知识和技能的能力以及许多脑部疾病的组成部分的基本过程。遗传工具已被广泛用于可塑性研究的每个领域。我们提出的研究将为神经科学社区提供一个转基因平台，以结合最先进的探针和工具，以监测和操纵细胞和亚细胞水平的可塑性。神经科学社区对这些遗传工具的使用将对可塑性在大脑功能和疾病中的作用的进一步理解产生重大影响，从而导致治疗疾病和改善公共卫生的方式。