Generation and analysis of FoxG1 transgenic mouse lines

FoxG1转基因小鼠品系的产生和分析

• 批准号: 8487472
• 负责人: Santosh R D'Mello
• 金额: $ 2.35万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8487472
• 关键词: Adult; Agreement; Alzheimer' s disease model; Animal Model; Brain; Breeding; CDK5 gene; Cessation of life; Connecticut; DNA; Development; Dominant-Negative Mutation; Family; Fee-for-Service Plans; Funding; Gene Targeting; Generations; Goals; Injection of therapeutic agent; Insulin-Like Growth Factor I; Laboratories; Maintenance; Medical center; Modeling; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oocytes; Pathway interactions; Prions; Proteins; Reagent; Signal Transduction; Sum; System; Testing; Transgenes; Transgenic Mice; Transgenic Organisms; Universities; Work; expression vector; falls; in vivo; insight; member; mouse model; mutant; neuron loss; neuronal survival; neuropathology; novel therapeutics; overexpression; prevent; promoter; research and development; tissue culture; transcription factor

DESCRIPTION (provided by applicant): Neurodegenerative diseases are characterized by the progressive and relentless loss of neurons. One strategy to prevent or slow down neurodegeneration is to stimulate molecules that have neuroprotective activity. Using tissue culture systems we have demonstrated that FoxG1, a member of the Forkhead family of transcription factors, is necessary for the maintenance of neuronal survival. Furthermore, elevated expression of FoxG1 has strong neuroprotective effects. We propose to extend our studies in vivo and predict that elevated levels of FoxG1 will be also be protective in animal models of neurodegenerative disease. We propose to test this prediction by generating transgenic mice that express elevated levels of FoxG1 selectively in neurons. These mice will be crossed with two different mouse models of neurodegenerative disease and the effect on progression of neuropathology evaluated. The two specific aims of this proposal are - Aim 1: To generate transgenic mice overexpressing wild-type FoxG1, a constitutively-active form of FoxG1, and a dominant-negative form of FoxG1. We will use the mouse prion protein (mPrP) promoter to drive expression of the three forms of FoxG1 in mice. Aim 2: Analysis of the effect of FoxG1 overexpression on the brain and in mouse models of neurodegeneration. We will examine the effect of increasing FoxG1 activity, through expression of WT and CA FoxG1, on neuronal survival in the normal brain. In a second part of this aim we will examine whether elevated FoxG1 activity protects mice against neurodegeneration. We will cross FoxG1-overexpressing transgenic mice with R6/2 mice (a model of HD) and with p25/CDK5 inducible-transgenic mice (a model of AD). The project will result in the development of three new mouse lines expressing wild-type and mutant FoxG1 transgenic mice. FoxG1 transgenic mice do not currently exist. We feel that generating these mice and testing whether elevated FoxG1 can protect against neurodegenerative disease will shed insight into the function of FoxG1 in postmitotic neurons in vivo and could identify it as a target for the development of novel therapeutic strategies for neurodegenerative disorders.

描述（由申请人提供）：神经退行性疾病的特征是神经元的进行性和持续性损失。预防或减缓神经退化的一种策略是刺激具有神经保护活性的分子。通过组织培养系统，我们已经证明FoxG1， Forkhead转录因子家族的成员，是维持神经元存活所必需的。此外，FoxG1表达升高具有较强的神经保护作用。我们建议在体内扩展我们的研究，并预测FoxG1水平升高也将对神经退行性疾病的动物模型具有保护作用。我们建议通过产生在神经元中选择性表达高水平FoxG1的转基因小鼠来验证这一预测。这些小鼠将与两种不同的神经退行性疾病小鼠模型杂交，并评估其对神经病理学进展的影响。该提案的两个具体目标是：目标1：产生过表达野生型FoxG1的转基因小鼠，FoxG1是FoxG1的组成活性形式，FoxG1是FoxG1的显性阴性形式。我们将使用小鼠朊蛋白（mPrP）启动子来驱动三种形式的FoxG1在小鼠中的表达。目的2：分析FoxG1过表达对脑及小鼠神经变性模型的影响。我们将通过WT和CA FoxG1的表达来研究FoxG1活性增加对正常大脑神经元存活的影响。在这个目标的第二部分，我们将研究FoxG1活性升高是否保护小鼠免受神经变性。我们将foxg1过表达转基因小鼠与R6/2小鼠（HD模型）和p25/CDK5诱导转基因小鼠（AD模型）杂交。该项目将开发出三种新的小鼠系，表达野生型和突变型FoxG1转基因小鼠。FoxG1转基因小鼠目前还不存在。我们认为，生成这些小鼠并测试FoxG1升高是否可以预防神经退行性疾病，将有助于深入了解FoxG1在体内有丝分裂后神经元中的功能，并可能将其作为开发神经退行性疾病新治疗策略的靶点。