CORE 1: Genetically Engineered Mice for Collaborations

核心 1：用于协作的基因工程小鼠

• 批准号: 7279788
• 负责人: SUSUMU TONEGAWA
• 金额: $ 27.65万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7279788
• 关键词: NMDA receptors; biomedical facility; dentate gyrus; gene targeting; genetic strain; genetically modified animals; glutamate receptor; hippocampus; interdisciplinary collaboration; laboratory mouse; learning; memory; neural plasticity; synapses

Many Individual Projects of the proposed Silvio O. Conte Center for Neuroscience Research (CCNR) at MIT utilize genetically engineered mice as key experimental tools. Most of these mouse strains are conditionally engineered (i.e., spatially and/or temporally restricted) and, hence, require state-of-the-art technology. The role of Core #1 is twofold: to provide the technical knowhow regarding the transgenics and knockout mice to the Center's individual laboratories and to generate some of the strains that are proposed to be used by the Center's multiple laboratories as multidisciplinary collaborations. In Specific Aims #1 to #3, the Cre-loxP recombination system will be combined with the tetracycline-transactivator (tTA) system to accomplish cell type-restricted, reversibly regulatable expression of a gene. Specific Aim #1 will attempt to regulate the NMDA receptor (NR)-1 gene in the dentate gyrus (DG) granule cells, while Specific Aim #2 will seek to regulate the GluR6 (G6) gene in the DG granule cells or CA3 pyramidal cells. These mutant mice provide invaluable tools in the Center's collaborative attempt (Individual Project #2) to understand the roles of synaptic plasticity in distinct hippocampal excitatory synapses in specific aspects of learning and memory. Specific Aim #3 will attempt to regulate the NR1 gene in the superficial layers of the entorhinal cortex and will serve the Center's collaborative effort (Individual Project #1) to understand the role of these receptors in place field formation. The objective of Specific Aim #4 is to produce a dorsal forebrain-restricted tTA mouse which is an important component mouse for the generation of multiple transgenic strains needed in the Center's collaborative attempt to understand how synaptic plasticity in the visual cortex subserves the receptive field plasticity (Individual Project #6). Core #1 will also provide training and the facility to Individual Project #7 which proposes to generate transgenic lines of PSD-GFP fusion proteins to study the morphological changes accompanying synaptic plasticity (Individual Project #7). Finally, Core #1 will provide advice and instructions to the attempt to genetically manipulate cortical function of monkeys (Individual Project #3).

Silvio O.麻省理工学院的康特神经科学研究中心（CCNR）利用基因工程小鼠作为关键的实验工具。这些小鼠品系中的大多数是条件工程化的（即，在空间和/或时间上受到限制），因此需要现有技术。核心1号的作用是双重的：向中心的各个实验室提供关于转基因和基因敲除小鼠的技术知识 并产生一些菌株，这些菌株将被该中心的多个实验室作为多学科合作使用。在特定目的#1至#3中，Cre-loxP重组系统将与四环素反式激活因子（tTA）系统组合以实现基因的细胞类型限制的可逆可调节表达。具体目标#1将尝试调节齿状回（DG）颗粒中的NMDA受体（NR）-1基因 具体目标#2将寻求调节DG颗粒细胞或CA 3锥体细胞中的GluR 6（G6）基因。这些突变小鼠在该中心的合作尝试（个人项目#2）中提供了宝贵的工具，以了解突触可塑性在学习和记忆的特定方面的不同海马兴奋性突触中的作用。具体目标#3将试图调节内嗅皮层浅层的NR 1基因，并将服务于中心的合作努力（个人项目#1），以了解这些受体在地方场形成中的作用。具体目标#4的目的是产生背侧前脑限制性tTA小鼠，这是产生中心合作尝试了解视觉皮层中突触可塑性如何促进感受野可塑性（个人项目#6）所需的多种转基因品系的重要组成小鼠。核心#1还将为个人项目#7提供培训和设施，该项目提出产生PSD-GFP融合蛋白的转基因系，以研究伴随突触可塑性的形态学变化（个人项目#7）。最后，核心#1将提供建议和指导，以试图从基因上操纵猴子的皮质功能（个人项目#3）。