Generation and analysis of FoxG1 transgenic mouse lines

描述（由申请人提供）：神经退行性疾病的特征在于神经元的进行性和无情的损失。预防或减缓神经变性的一种策略是刺激具有神经保护活性的分子。使用组织培养系统，我们已经证明，FoxG 1，叉头家族的转录因子的成员，是必要的维持神经元的存活。此外，FoxG 1的表达升高具有强烈的神经保护作用。我们建议扩展我们的体内研究，并预测FoxG 1水平升高也将在神经退行性疾病的动物模型中起到保护作用。我们建议通过产生在神经元中选择性表达高水平FoxG 1的转基因小鼠来测试这一预测。将这些小鼠与两种不同的神经退行性疾病小鼠模型杂交，并评价对神经病理学进展的影响。该提议的两个具体目标是-目标1：产生过表达野生型FoxG 1、FoxG 1的组成型活性形式和FoxG 1的显性阴性形式的转基因小鼠。我们将使用小鼠朊蛋白（mPrP）启动子来驱动小鼠中FoxG 1的三种形式的表达。目的2：分析FoxG 1过表达对脑和小鼠神经退行性变模型的影响。我们将研究通过WT和CA FoxG 1表达增加FoxG 1活性对正常脑中神经元存活的影响。在这个目标的第二部分，我们将研究FoxG 1活性升高是否能保护小鼠免受神经退行性变。我们将FoxG 1过表达转基因小鼠与R6/2小鼠（HD模型）和p25/CDK 5诱导转基因小鼠（AD模型）杂交。该项目将导致三个新的小鼠品系表达野生型和突变型FoxG 1转基因小鼠的发展。FoxG 1转基因小鼠目前还不存在。我们认为，产生这些小鼠并测试升高的FoxG 1是否可以预防神经退行性疾病，将深入了解FoxG 1在体内有丝分裂后神经元中的功能，并可以将其确定为神经退行性疾病新治疗策略的开发目标。

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.