Small molecule mitochondria-targeted therapeutics for Huntingtons Disease

我们建议测试将重点从压力反应转移到压力弹性的方法，以及促进- 治疗神经退行性变的神经保护性治疗方法的研究进展 高清等订单。我们证明，部分抑制线粒体复合体I的活性与小分子- 我们实验室开发的CULES诱导了多种与机制重叠的抗逆性机制-- 长寿的象征。这些小分子穿透血脑屏障，积聚在线粒体中。 其中它们部分抑制线粒体复合体的活性。I.对这种轻度应激的适应性反应 结果在激活诱导对氧化应激的保护的分子机制中，内毒素-2. 增强细胞能量学，恢复轴突运输，保护突触完整性和功能。 提顿。使用这些策略的神经保护在多种阿尔茨海默病小鼠模型中得到证实 (AD)，按时间顺序老化的小鼠，以高脂饮食喂养的野生型小鼠，以及人类神经元和纤维- 阿尔茨海默病和线粒体疾病患者的原始细胞。在表达截短和全长的小鼠神经元中 突变的Huntingtin(MHTT)蛋白，用部分复合体I抑制剂处理后，mHTT聚集性显著降低。 抑制，恢复改变的胆固醇稳态和内吞作用。在R6/2小鼠中，这种治疗延长了 活体，减少紧握表型和癫痫发作事件。我们的最终目标是发展一种疾病- 修改HD的治疗方法。本提案的目标是建立概念证据，证明PAR的应用- TiAl复合体I抑制剂在人类和小鼠HD模型中提供神经保护，并获得对 神经保护的关键分子机制。根据我们的初步数据和一个事实，有丝分裂- AL功能障碍和氧化应激增加有助于HD的机制，我们建议检验一个假说 部分复合体I类抑制剂的应用可延缓HD的发生发展，对HD具有保护作用 改善线粒体动力学和功能，提高抗氧化能力导致的神经元损伤 压力。具体的实验目标是：1)调查线粒体的慢性给药 部分复合体I抑制剂延缓细菌人工染色体HD的发生和发展 (2)确定雄性和雌性最佳治疗机会窗 BACHD小鼠；(3)建立不同时期神经保护分子机制的层级 疾病的不同阶段；(4)使用人类HD细胞来展示这种方法的翻译潜力。 拟议的研究基于强有力的前提，并将使用inno-in对该假设进行严格的检验。 创新细胞生物学、生物化学、系统生物学和成像技术、药理学和遗传学 干预措施。这些结果将提供关键的生物学证据，以建立理论基础和前 支持HD特异性线粒体复合体I抑制剂进一步临床开发的临床标准 治疗。自从专有的部分复合体I类抑制剂作为一流的疾病改良剂开发以来 神经退行性疾病的治疗策略目前在我们实验室处于领先优化的后期阶段， 这项提议的结果可以证明对HD应用这一新战略是合理的，大大缩短了 从发现到临床应用于人类的时间。

We propose to test the approach that shifts the focus from stress response to stress resilience, and the facilita- tion of neuroprotective therapeutic processes that may serve as effective treatment in neurodegenerative dis- orders such as HD. We demonstrated that partial inhibition of mitochondrial complex I activity with small mole- cules developed in our laboratory induces multiple mechanisms of stress resilience that overlap with mecha- nisms of longevity. These small molecules penetrate the blood brain barrier and accumulate in mitochondria where they partially inhibit the activity of mitochondrial complex I. The adaptive response to this mild stress re- sults in the activation of molecular mechanisms that induce a protection against oxidative stress, the en- hancement of cellular energetics, restoration of axonal trafficking and protection of synaptic integrity and func- tion. Neuroprotection using these strategy was confirmed in multiple mouse models of Alzheimer's Disease (AD), chronologically aged mice, in wild type mice fed with a high fat diet, and in human neurons and fibro- blasts from patients with AD and mitochondria disease. In mouse neurons expressing truncated and full-length mutant Huntingtin (mHtt) protein, treatment with partial complex I inhibitors significantly reduced mHtt aggrega- tion, restored altered cholesterol homeostasis and endocytosis. In R6/2mice, this treatment extended the sur- vival, and reduced clasping phenotype and incidents of seizures. Our ultimate goal is to develop a disease- modifying treatment for HD. Objectives of this proposal are to establish proof of concept that application of par- tial complex I inhibitors provides neuroprotection in human and mouse models of HD, and to gain the insight in critical molecular mechanisms of neuroprotection. Based on our preliminary data and the fact that mitochondri- al dysfunction and increased oxidative stress contribute to HD mechanism, we propose to test a hypothesis that application of partial complex I inhibitors could delay the onset and development of HD and protect against neuronal loss by improving mitochondrial dynamics and function and increasing the resistance to oxidative stress. The specific experimental goals are: 1) to investigate whether chronic administration of mitochondrial partial complex I inhibitor delays the onset and development of HD in bacterial artificial chromosome HD (BACHD) transgenic mice; (2) to determine the best window of therapeutic opportunity in male and female BACHD mice; (3) to establish the hierarchy of molecular mechanisms involved in neuroprotection at different stages of the disease; (4) to demonstrate the translational potential of this approach using human HD cells. The proposed studies are based on strong premise and will provide rigorous test of the hypothesis using inno- vative cell biology, biochemistry, systems biology and imaging techniques, and pharmacological and genetic interventions. The outcomes will provide the critical biological evidence to establish the rationale and the pre- clinical criteria, to support further clinical development of specific mitochondrial complex I inhibitors for HD treatment. Since the development of proprietary partial complex I inhibitors as a first in class disease modifying strategy for neurodegenerative diseases is currently in advanced stage of lead optimization in our laboratory, the outcomes of this proposal could justify the application of this new strategy for HD significantly shortening the time from the discovery to the clinical application in humans.