Targeting REV-ERB regulation of mitochondria as a therapeutic strategy in Alzheimer's disease

靶向线粒体 REV-ERB 调节作为阿尔茨海默病的治疗策略

基本信息

批准号：
9812751
负责人：
Jaymie Voorhees
金额：
$ 6.43万
依托单位：
ST. LOUIS COLLEGE OF PHARMACY
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：
2018-09-27 至 2021-09-26
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9812751
关键词：
Affect Agonist Alzheimer&apos s Disease Alzheimer&apos s disease model Animal Disease Models Automobile Driving Bioenergetics Brain Brain Diseases Cause of Death Cell Culture Techniques Cell Survival Cells Circadian Rhythms Cognitive Cognitive deficits Data Deposition Diagnosis Disease Elements Energy Metabolism Gene Expression Genes Genetic Models Genetic Transcription Goals Health Hippocampus (Brain)Impaired cognition Impairment Incidence Individual Metabolism Mitochondria Mus Neurofibrillary Tangles Nuclear Receptors Organelles Oxidative Stress Pathologic Pathway interactions Patients Pharmacology Physiological Physiological Processes Public Health Regulation Research Role Senile Plaques Therapeutic United States Wild Type Mouse brain cell effective therapy experience extracellular immune health improved lipid biosynthesis mouse model nervous system disorder neurofibrillary tangle formation neuroinflammation neuron loss novel novel therapeutics pre-clinical preservation prevent tau Proteins therapeutic target treatment strategy

项目摘要

PROJECT SUMMARY Alzheimer's disease (AD) is a devastating neurologic disorder that affects millions of people worldwide. In the United States, over 5 million people are currently living with AD, and it is the 6th leading cause of death. Despite decades of intensive research, effective treatment strategies are lacking, and with the incidence expected to rise in the coming decades, there is a significant unmet need for novel AD therapeutics. The hallmarks of AD include extracellular amyloid plaque deposition, intracellular tau hyperphosphorylation leading to neurofibrillary tangle formation, neuroinflammation, and ultimately, neuron cell loss. Although the mechanisms driving these hallmarks are not entirely clear, it is generally accepted that each of these pathophysiological hallmarks is deleterious, and together, they precipitate devastating cognitive and psychiatric impairments. In addition to the pathological hallmarks of AD, some basic pathophysiological disturbances are also present. Mitochondrial function, which is critical for cell health, is one of these physiological processes commonly perturbed in patients with AD and animal models of the disease. Under normal physiological circumstances, mitochondria are essential for energy metabolism, however in diseased states, mitochondria become inefficient, oxidative stress increases, and cellular damage is inevitable. In AD, mitochondria are highly dysregulated and become increasingly dysfunctional. Interestingly, circadian rhythm, which is also perturbed in patients with AD, greatly influences mitochondrial function. Indeed, the nuclear receptor REV-ERB, which is a critical transcriptional regulator of circadian rhythm, has been shown to control mitochondrial function and energy metabolism. Thus, I hypothesize that REV-ERB is an important regulator of bioenergetics, and therefore, pharmacological activation can be used to control mitochondrial function and protect against cellular energy deficits in AD. Furthermore, this preservation of energy dynamics in AD could prevent or improve cognitive and psychiatric impairments in the disease. To this end, the research proposed here will aim to 1) elucidate the mechanism(s) governing REV-ERB regulation over bioenergetics and 2) investigate the efficacy of pharmacological activation of REV-ERB to mitigate bioenergetics deficiencies and ensuing cognitive impairment in a preclinical genetic model of AD. These studies will advance our understanding of REV-ERB function in the brain and provide the basis for a novel therapeutic strategy in the treatment for Alzheimer's disease.

项目概要阿尔茨海默病 (AD) 是一种毁灭性的神经系统疾病，影响着全世界数百万人。在在美国，目前有超过 500 万人患有 AD，这是导致 AD 的第六大原因死亡。尽管进行了数十年的深入研究，但仍缺乏有效的治疗策略，并且随着预计未来几十年发病率将上升，对新型 AD 的需求显着未得到满足疗法。 AD 的标志包括细胞外淀粉样斑块沉积、细胞内 tau 过度磷酸化导致神经原纤维缠结形成、神经炎症，并最终，神经元细胞损失。尽管驱动这些特征的机制尚不完全清楚，但人们普遍认为这些病理生理学特征中的每一个都是有害的，并且它们一起导致毁灭性的认知和精神障碍。除了 AD 的病理特征外，还存在一些基本的病理生理学紊乱。线粒体功能对细胞至关重要健康是 AD 患者和动物中通常受到干扰的生理过程之一该疾病的模型。正常生理情况下，线粒体对于能量至关重要然而，在疾病状态下，线粒体的新陈代谢效率降低，氧化应激增加，并且细胞损伤是不可避免的。在 AD 中，线粒体高度失调并且变得越来越功能失调。有趣的是，昼夜节律在 AD 患者中也受到干扰，对 AD 患者的影响很大。线粒体功能。事实上，核受体 REV-ERB 是一个关键的转录调节因子。昼夜节律已被证明可以控制线粒体功能和能量代谢。于是，我假设 REV-ERB 是生物能学的重要调节剂，因此，药理学激活可用于控制线粒体功能并防止 AD 中的细胞能量不足。此外，AD 中这种能量动态的保存可以预防或改善认知能力和该疾病的精神障碍。为此，本文提出的研究旨在 1）阐明控制 REV-ERB 对生物能量学的调节的机制，以及 2）研究其功效 REV-ERB 的药理激活可减轻生物能缺陷和随之而来的认知障碍 AD 临床前遗传模型的损伤。这些研究将增进我们对 REV-ERB 的理解大脑功能并为治疗阿尔茨海默病的新治疗策略提供基础疾病。