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

ARE 介导的基因表达在亨廷顿病中的治疗潜力

• 批准号: 7981119
• 负责人: KARI RENE HOYT
• 金额: $ 45.75万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7981119
• 关键词: Academic Research Enhancement Awards; Affect; Antioxidants; Attenuated; Behavioral Research; Behavioral Sciences; Binding; Binding Proteins; Biogenesis; Biological Assay; Brain; Brain Pathology; Breeding; Cells; Code; Data; Data Set; Development; Disease Progression; Doxycycline; Drug Design; Drug Metabolic Detoxication; Eligibility Determination; Enhancers; Environment; Enzymes; Event; Exposure to; Extramural Activities; Feasibility Studies; Future; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Glial Fibrillary Acidic Protein; Goals; Grant; Huntington Disease; Image; Imagery; Indium; Institution; Label; Lead; Lipids; Mediating; Mediator of activation protein; Metabolic; Mitochondria; Motor; Mouse Strains; Mus; NIH Program Announcements; Neuroglia; Neurons; Nickel; Nucleic Acids; Ohio; Oxidative Stress; Pathology; Pathway interactions; Patients; Pattern; Pharmacy facility; Phase; Population; Process; Prosencephalon; Proteins; Qualifying; Reactive Oxygen Species; Regulation; Relative (related person); Research; Research Personnel; Research Project Grants; Research Technics; Resources; Response Elements; Role; Scheme; Scientist; Signal Transduction; Site; Students; Symptoms; System; Technology; Testing; Tetracyclines; Therapeutic; Toxic effect; Training; Trans-Activators; Transcript; Transgenes; Transgenic Mice; Transgenic Organisms; United States National Institutes of Health; Universities; Up-Regulation; Work; base; cell type; college; cytotoxic; design; design and construction; experience; human Huntingtin protein; mouse model; new therapeutic target; novel; polyglutamine; programs; promoter; public health relevance; research study; response; therapeutic target; transcription factor; transgene expression

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.

描述（由申请人提供）：该 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。它们驱动 II 相解毒/抗氧化酶的表达，因此可能是减轻活性氧 (ROS) 诱导的细胞毒性的有效治疗靶点，而活性氧是 HD 发展的潜在因素。为此，我们培育了一种新型转基因小鼠品系，其中转录因子 Nrf2 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 Nrf2 和 MafK 的细胞类型特异性表达，从而增加 II 相解毒/抗氧化酶的表达。在目标 1 中，我们将在 HD 的 R6/2 小鼠模型中测试 ARE 介导的基因表达的神经保护作用。在目标 2 中，我们将对 R6/2 小鼠中基础和转基因诱导的 Nrf2-ARE 转录途径激活进行系统分析。总体而言，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 的可行的预防或治疗方法。我们的结果还应该有助于确定未来药物设计的新的、潜在的细胞保护靶点。 公共健康相关性：我们的工作基于这样的观点：氧化应激会导致亨廷顿病的神经元损伤，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神经元损伤的保护。这项工作的结果将有助于未来 HD 神经保护疗法的设计。