Bioenergetics in Animal Models of Huntington's Disease

亨廷顿病动物模型中的生物能学

• 批准号: 6702561
• 负责人: M FLINT BEAL
• 金额: $ 36.96万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-15 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6702561
• 关键词: Huntington' s disease; PC12 cells; amidohydrolases; bioenergetics; cAMP response element binding protein; creatine; cyclic AMP; cytotoxicity; enzyme inhibitors; gene expression; genetic models; genetic transcription; genetically modified animals; immunocytochemistry; laboratory mouse; mitochondrial disease /disorder; neuroprotectants; oxidative phosphorylation; oxidative stress; phosphodiesterase inhibitors; tissue /cell culture; ubiquinone; western blottings

DESCRIPTION (provided by applicant): The pathogenesis of Huntington's Disease (HD) is as yet unknown but there is substantial evidence that both altered gene transcription as well as mitochondrial dysfunction play an important role. There is evidence that huntingtin binds to transcription factors which results in decreased expression of genes which may play a critical role in neuronal survival. A secondary consequence of this appears to be impaired oxidative phosphorylation and increased generation of reactive oxygen species. In our prior grant, we showed that there was impaired oxidative phosphorylation in transgenic mouse models of Huntington's disease, and that this was associated with increased oxidative damage. We also showed that agents such as creatine and coenzyme Q, which improve cellular bioenergetics, exert neuroprotective effects in transgenic mouse models of Huntington's disease. In the present proposal, we intend to extend these studies to two further unique transgenic mouse models of Huntington's disease. We will determine whether there is mitochondrial dysfunction and oxidative damage in a knock-in mouse model developed by MacDonald and colleagues. These mice are a very accurate genetic model of Huntington's disease. We will also examine the tetracycline-off model developed by Yamamoto and colleagues to determine whether there is mitochondrial dysfunction and oxidative damage with the gene turned on, which then resolves once the gone is turned off. We will carry out similar studies with an inducible cell culture model. We will investigate whether histone deacetylase (HDAC) inhibitors exert neuroprotective effects by altering gene transcription in transgenic mouse models of Huntington's disease. We will examine whether a phosphodiesterase IV inhibitor can exert neuroprotective effects in transgenic mouse models of HD by increasing cyclic AMP levels, leading to increased CREB transcriptional activity, and whether this improves mitochondrial function. Our prior studies showed that combinations of agents, which target different disease mechanisms in Huntington's disease, may exert additive neuroprotective effects. We will, therefore, examine whether a combination of creatine or coenzyme Q with either a HDAC inhibitor or a phosphodiesterase IV inhibitor can exert additive neuroprotective effects.

描述（由申请人提供）：亨廷顿病（HD）的发病机制尚不清楚，但有大量证据表明基因转录的改变以及线粒体功能障碍发挥着重要作用。有证据表明亨廷顿蛋白与转录因子结合，导致基因表达减少，而这些基因可能在神经元存活中发挥关键作用。其第二个后果似乎是氧化磷酸化受损和活性氧的产生增加。在我们之前的资助中，我们表明亨廷顿病转基因小鼠模型中氧化磷酸化受损，并且这与氧化损伤增加有关。我们还表明，肌酸和辅酶 Q 等可改善细胞生物能量的药物在亨廷顿病转基因小鼠模型中发挥神经保护作用。在目前的提案中，我们打算将这些研究扩展到另外两种独特的亨廷顿病转基因小鼠模型。我们将确定麦克唐纳及其同事开发的基因敲入小鼠模型中是否存在线粒体功能障碍和氧化损伤。这些小鼠是亨廷顿舞蹈症非常准确的遗传模型。我们还将检查山本及其同事开发的四环素关闭模型，以确定该基因打开时是否存在线粒体功能障碍和氧化损伤，然后一旦关闭该基因，这些问题就会解决。我们将利用诱导细胞培养模型进行类似的研究。我们将研究组蛋白脱乙酰酶 (HDAC) 抑制剂是否通过改变亨廷顿病转基因小鼠模型中的基因转录来发挥神经保护作用。我们将研究磷酸二酯酶 IV 抑制剂是否可以通过增加环 AMP 水平，导致 CREB ​​转录活性增加，从而在 HD 转基因小鼠模型中发挥神经保护作用，以及这是否可以改善线粒体功能。我们之前的研究表明，针对亨廷顿病不同疾病机制的药物组合可能会发挥额外的神经保护作用。因此，我们将研究肌酸或辅酶 Q 与 HDAC 抑制剂或磷酸二酯酶 IV 抑制剂的组合是否可以发挥附加的神经保护作用。