Transgenic animal models for neuroscience research

用于神经科学研究的转基因动物模型

• 批准号: 7970150
• 负责人: James Pickel
• 金额: $ 180.38万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 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/7970150
• 关键词: Adult; Affect; Age; Alleles; Animal Model; Animals; Area; Behavior; Behavioral; Biochemical; Brain; Calcium; Cells; Cellular biology; Collaborations; Collection; Complex; Core Facility; Development; Disease; Disease model; Embryo; Engineering; Enterobacteria phage P1 Cre recombinase; Extramural Activities; Familial Dysautonomia; Freezing; Frequencies; Fright; Ganglioside Sialidase Deficiency Disease; Gene Expression; Genes; Human; Information Resources; Institutes; Intramural Research Program; Investigation; Laboratories; Learning; Link; Memory; Mental disorders; Methyltransferase; Mission; Mus; Mutation; National Institute of Mental Health; Neurodegenerative Disorders; Neuroglia; Neurons; Neuropathy; Neurosciences; Neurosciences Research; Peptides; Predisposition; Pregnancy; Property; Protein Biosynthesis; Rattus; Reporter; Reporting; Research; Research Personnel; Research Project Grants; Role; Scientist; Services; Stress; Technical Expertise; Techniques; Testing; Transgenes; Transgenic Animals; Transgenic Mice; Transgenic Organisms; United States National Institutes of Health; addiction; embryonic stem cell; gene function; human disease; interest; mouse model; nervous system disorder; neural circuit; neurodevelopment; neurogenesis; programs; recombinase; reconstitution; relating to nervous system; repository; research study; sperm cell; tool

The potential associations between human genes and mental disorders are being increasingly identified. But with these associations comes a conspicuous lack of understanding of how these genes function in an afflicted, or even a presumably normal brain. By creating animals with the same genetic changes and even some carrying human disease genes these associations can be tested. By producing mice with human disease alleles neuroscientists can study the behavioral, developmental, anatomical, cellular and biochemical levels of the disease. From this approach the normal function of these genes can be defined. This approach has been used to provide animal models for many research projects at the NIH IRP as well as with collaborators in the extramural program. The details of these experiments are described in investigators own reports. Below is a partial list of our research projects that suggests the scope of the areas of investigations that have benefited from animal models produced by the core facility. These projects cover a wide range of neuroscience experiments at the level of specific molecules, gene expression, cell biology, neural circuits, learning, complex behavior, and include studies of specific diseases. Stress: the role of a specific gene (catachol-O-methyltransferase) in the susceptibility to stress was demonstrated in mice that were engineered to have reduced levels of this gene. Learning and memory: In the past year transgenic mouse models have been used to show the role of specific protein synthesis on learning and memory. Other transgenic mouse models have been used to show the role of specific peptide-expressing cells to influence the link between fear and behavior and learning. Neurogenesis: From mid-gestation and into old age, new neurons are produced in the brain. The role of these new cells that appear in adults is especially interesting, and suggests a function in learning and memory and potential treatments for neurodegenerative disorders. Mucolipidosis IV: The mouse model of this disease resulted from a long-standing collaboration with the Slaugenhaupt laboratory and has continued to yield results, including a description of the neuropathy that may be associated with this disease. The core facility continues to distribute these animals. Familial dysautonomia: Another collaboration with the Slaugenhaupt lab resulted in a model for this disease. The lines that carry either a human normal or disease gene are being created in the core. Those are crossed into a null line to replace the endogenous IKBKAP gene with its human disease equivalent. The core produced several new lines this year to test the effect of multiple copies of the gene. Activity in glial cells: The core produced a mouse line with a transgene that indicated the concentration of calcium in glial cells. By changes in its fluorescent properties the calcium concentration, and associated activity, has been demonstrated in these cells. Manipulating circuitry: Mice in which specific neurons could be rendered transiently inactive have been produced for two separate laboratories. Those laboratories are investigating different neural circuits that are active in learning and addiction. Reporter and effector mice: Several lines that express effector molecules like CRE recombinase at specific temporal and spatial compartments were produced. Other lines that were used to report the activity of these and other recombinases were created. Mice, such as those from the Gensat project were rederived and exported. Transgenic rats: Technological development projects have allowed the core to produce transgenic rats for investigators in three NIH intramural institutes.

人类基因和精神疾病之间的潜在联系越来越多地被确定。但是，伴随着这些关联而来的是对这些基因在患病大脑中如何发挥作用的明显缺乏了解，甚至是一个可能正常的大脑。通过创造具有相同基因变化的动物，甚至一些携带人类疾病基因的动物，这些关联可以得到测试。通过制造带有人类疾病等位基因的小鼠，神经科学家可以研究疾病的行为，发育，解剖，细胞和生化水平。通过这种方法，可以确定这些基因的正常功能。这种方法已被用于为NIH IRP的许多研究项目提供动物模型，以及与校外项目的合作者。这些实验的细节在研究人员自己的报告中有描述。 以下是我们研究项目的部分列表，表明了从核心设施生产的动物模型中受益的研究领域的范围。这些项目涵盖了特定分子、基因表达、细胞生物学、神经回路、学习、复杂行为等层面的广泛神经科学实验，并包括特定疾病的研究。 压力：一种特定基因（catachol-O-甲基转移酶）在对应激的易感性中的作用在被改造为具有降低水平的该基因的小鼠中得到证实。 学习和记忆：在过去的一年中，转基因小鼠模型已被用于显示特定蛋白质合成对学习和记忆的作用。其他转基因小鼠模型已被用于显示特定肽表达细胞的作用，以影响恐惧与行为和学习之间的联系。 神经发生：从妊娠中期到老年，大脑中产生新的神经元。这些出现在成年人中的新细胞的作用特别有趣，并表明了学习和记忆功能以及神经退行性疾病的潜在治疗方法。 粘脂病IV：这种疾病的小鼠模型来自与Slaugenhaupt实验室的长期合作，并继续产生结果，包括可能与这种疾病相关的神经病变的描述。核心设施继续分发这些动物。 家族性自主神经功能障碍：与Slaugenhaupt实验室的另一项合作导致了这种疾病的模型。携带人类正常基因或疾病基因的细胞系正在核心中产生。这些基因被杂交到一个空系中，以用其人类疾病等价物取代内源性IKBKAP基因。核心今年生产了几个新的品系，以测试多个基因拷贝的效果。 在神经胶质细胞中的活性：核心产生了一种具有转基因的小鼠品系，该转基因指示了神经胶质细胞中的钙浓度。通过其荧光特性的变化，已经在这些细胞中证明了钙浓度和相关活性。 操纵电路：已经为两个不同的实验室生产了可以使特定神经元暂时失活的小鼠。这些实验室正在研究在学习和成瘾中活跃的不同神经回路。 报告和效应小鼠：产生了在特定时间和空间区室表达效应分子如CRE重组酶的几个系。创建了用于报告这些和其他重组酶的活性的其他系。小鼠，如来自Gensat项目的小鼠，被重新衍生和出口。 转基因大鼠：技术开发项目使核心能够为三个NIH内部研究所的研究人员生产转基因大鼠。