Therapeutic potential of ARE-mediated gene expression in Huntington's disease

描述（由申请人提供）：本R15 AREA提案的总体目标是测试抗氧化反应元件（ARE）介导的基因表达是否对亨廷顿病（HD）具有神经保护作用。该区域驱动II相解毒/抗氧化酶的表达，因此，可能是减弱活性氧（ROS）诱导的细胞毒性的有效治疗靶点，这是HD发展中的潜在因素。为此，我们产生了一种新型转基因小鼠品系，其中转录因子Nrf 2和MafK在前脑神经元或神经胶质细胞内以四环素诱导的方式驱动。我们将这些新的转基因小鼠与成熟的HD转基因小鼠模型（R6/2系）杂交，以驱动Nrf 2和MafK的细胞类型特异性表达，从而增加II期解毒/抗氧化酶的表达。在目的1中，我们将测试ARE介导的基因表达在HD的R6/2小鼠模型中的神经保护作用。在目标2中，我们将在R6/2小鼠中对基础和转基因诱导的Nrf 2-ARE转录途径激活进行系统分析。总的来说，我们在本提案中概述的方法将使我们能够发现ARE介导的基因表达上调是否是治疗HD的可行预防或治疗方法。我们的研究结果还将为未来的药物设计确定新的、潜在的细胞保护靶点。 公共卫生相关性：我们的工作是基于氧化应激有助于亨廷顿病的神经元损伤的想法，我们的目标是发现是否有可能激活内源性抗氧化防御系统并实现对神经元损伤的保护。这项工作的结果将有助于未来设计的神经保护疗法的HD。

DESCRIPTION (provided by applicant): The overall goal of this R15 AREA proposal is to test whether Antioxidant Response Element (ARE)-mediated gene expression is neuroprotective in Huntington's disease (HD). The are drives the expression of phase II detoxifying/antioxidant enzymes, and as such, may be an effective therapeutic target to attenuate reactive oxygen species (ROS)-induced cell toxicity, which is an underlying element in the development of HD. To this end, we have generated a novel transgenic mouse strain where the are transcription factors Nrf2 and MafK are driven in a tetracycline-inducible manner within forebrain neurons or glia. We will cross these new transgenic mice with a well-established transgenic mouse model of HD (the R6/2 line) to drive cell-type specific expression of Nrf2 and MafK and thereby increase the expression of phase II detoxifying/antioxidant enzymes. In Aim 1, we will test the neuroprotective effects of ARE-mediated gene expression in the R6/2 mouse model of HD. In Aim 2, we will perform a systematic analysis of basal and transgenically-induced Nrf2-ARE transcriptional pathway activation in the R6/2 mouse. Overall, the approach we have outlined in this proposal will allow us to discover whether up-regulation of ARE-mediated gene expression is a viable preventative or therapeutic approach for the treatment of HD. Our results should also lead to the identification of new, potentially cytoprotective, targets for future drug design. PUBLIC HEALTH RELEVANCE: Our work is based on the idea that oxidative stress contributes to neuronal damage in Huntington's disease, and our goal is to discover whether it is possible to activate endogenous antioxidant defense systems and achieve protection from neuronal damage. The results of this work will contribute to the future design of neuroprotective therapies for HD.