Small molecule mitochondria-targeted therapeutics for Huntingtons Disease

亨廷顿病的小分子线粒体靶向疗法

基本信息

批准号：
10160973
负责人：
Eugenia Trushina
金额：
$ 53.51万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-15 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10160973
关键词：
Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Animal Model Autophagocytosis Axon Bacterial Artificial Chromosomes Behavior Biochemistry Biogenesis Biological Biological Models Blood - brain barrier anatomy Brain Brain-Derived Neurotrophic Factor Caloric Restriction Cells Cellular biology Cholesterol Homeostasis Chronic Chronology Code Complex Corpus striatum structure Data Development Diabetes Mellitus Disease Disease model Elderly Endocytosis Evaluation FDA approved Female Fibroblasts Functional disorder Genetic Goals Health High Fat Diet Homeostasis Human Huntington Disease Huntington gene Huntington protein Imaging Techniques Inflammation Laboratories Length Lipids Longevity Metabolic Metformin Mitochondria Mitochondrial Diseases Molecular Mus Names Nerve Degeneration Neurodegenerative Disorders Neurons Outcome Oxidative Phosphorylation Oxidative Stress Paper Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phenotype Population Process Proteins Pyrones Resistance Resveratrol Safety Seizures Stress Synapses Systems Biology Techniques Testing Therapeutic Time Transgenic Mice Translations Treatment Efficacy Wild Type Mouse aged base biological adaptation to stress clinical application clinical development cognitive function cohort effective therapy efficacy evaluation gene therapy human model improved in vivo inhibitor/antagonist innovation insight lead optimization male mitochondrial DNA mutation mitochondrial dysfunction mouse model multimodality mutant neuron loss neuroprotection novel therapeutic intervention obesity prevention pre-clinical response restoration small molecule stress resilience synaptic function targeted treatment trafficking

项目摘要

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.

我们建议测试将重点从压力反应转变为压力韧性的方法，以及主持人神经保护性治疗过程的影响，可以作为神经退行性疾病的有效治疗诸如高清订单。我们证明了对线粒体复合物I活性的部分抑制作用在我们的实验室中开发的Cules诱导了多种压力弹性机制，这些机制与机甲重叠长寿的态度。这些小分子穿透了血脑屏障并在线粒体中积聚它们部分抑制线粒体复合物的活性I.对这种轻度应激的适应性反应在激活分子机制的激活中，诱导氧化应激的保护细胞能量学，轴突贩运的恢复以及突触完整性和功能的保护 tion。在阿尔茨海默氏病的多种小鼠模型中证实了使用这些策略的神经保护作用（AD），按年代老化的小鼠，喂养高脂肪饮食的野生型小鼠，在人类神经元和纤维中 AD和线粒体疾病患者的爆炸。在表达截短且全长的小鼠神经元中突变的亨廷顿蛋白（MHTT）蛋白，用部分复合物I抑制剂处理显着降低MHTT聚集修复的胆固醇稳态和内吞作用改变了。在R6/2MICE中，这种处理扩展了 VIVAL，减少了扣型表型和癫痫发作的事件。我们的最终目标是发展一种疾病 - 修改高清治疗。该提案的目标是建立概念证明，以证明 TIAL复合物I抑制剂可在HD的人和小鼠模型中提供神经保护作用，并获得洞察力神经保护的关键分子机制。根据我们的初步数据以及线粒体的事实 Al功能障碍和增加的氧化应激有助于HD机制，我们建议检验假设局部复合物I抑制剂的应用可能会延迟HD的发作和发展，并防止神经元丧失通过改善线粒体动力学和功能，并增加对氧化的抗性压力。具体的实验目标是：1）研究线粒体长期给药是否部分复合物I抑制剂延迟细菌人工染色体HD中HD的发作和发展（Bachd）转基因小鼠；（2）确定男性和女性的最佳治疗机会窗口 Bachd小鼠；（3）建立在不同的分子机制的层次结构疾病的阶段；（4）使用人类HD细胞来证明这种方法的翻译潜力。拟议的研究是基于强大的前提，将对假设进行严格的检验养细胞生物学，生物化学，系统生物学和成像技术以及药理和遗传学干预措施。结果将提供关键的生物学证据，以建立理由和前临床标准，支持特定线粒体复合物I抑制剂的进一步临床开发治疗。自专有部分复合物I抑制剂的发展以来神经退行性疾病的策略目前处于我们实验室铅优化的高级阶段，该提案的结果可以证明该新策略在高清方面的应用是合理的。从发现到人类临床应用的时间。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A comprehensive protocol for multiplatform metabolomics analysis in patient-derived skin fibroblasts.

DOI：
10.1007/s11306-019-1544-z
发表时间：
2019-05-23
期刊：
Metabolomics : Official journal of the Metabolomic Society
影响因子：
0
作者：
Wilkins J;Sakrikar D;Petterson XM;Lanza IR;Trushina E
通讯作者：
Trushina E

Partial Inhibition of Mitochondrial Complex I Reduces Tau Pathology and Improves Energy Homeostasis and Synaptic Function in 3xTg-AD Mice.

DOI：
10.3233/jad-201015
发表时间：
2021
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
0
作者：
Stojakovic A;Chang SY;Nesbitt J;Pichurin NP;Ostroot MA;Aikawa T;Kanekiyo T;Trushina E
通讯作者：
Trushina E