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：
10400489
负责人：
Jaymie Voorhees
金额：
$ 5.16万
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 2022-06-03
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10400489
关键词：
Affect Agonist Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease therapeutic Animal Disease Models Automobile Driving Bioenergetics Brain 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 Molecular Mus Neurofibrillary Tangles Nuclear Receptors Organelles Oxidative Stress Pathologic Pathway interactions Patients Pharmacology Physiological Physiological Processes Pre-Clinical Model Public Health Regulation Research Role Senile Plaques Therapeutic United States Wild Type Mouse brain cell cell injury effective therapy efficacy evaluation experience extracellular immune health improved lipid biosynthesis mouse model nervous system disorder neurofibrillary tangle formation neuroinflammation neuron loss novel novel therapeutic intervention pre-clinical 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 mitochondria. 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, we hypothesize that REV-ERB is a critical regulator of bioenergetics, and therefore, pharmacological activation can be used to control mitochondrial function and protect against cellular energy deficits in AD. To this end, the research proposed here will aim to 1) elucidate molecular mechanisms employed by REV-ERB to modulate mitochondrial function and 2) determine the efficacy of pharmacological activation of REV-ERB as a therapeutic strategy targeting bioenergetic deficiencies in preclinical models of AD. We predict that 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。在美国，目前有超过 500 万人患有 AD，这是第六大死因。尽管进行了数十年的深入研究，但仍缺乏有效的治疗策略，并且发病率预计在未来几十年内将会增加，因此对新型 AD 疗法的需求尚未得到满足。 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的形成、神经炎症，并最终导致神经元细胞损失。驱动这些特征的机制尚不完全清楚，但人们普遍认为这些特征中的每一个病理生理学特征是有害的，它们共同导致毁灭性的认知和精神疾病除了 AD 的病理特征外，还有一些基本的病理生理障碍。对细胞健康至关重要的线粒体功能也是这些生理过程之一。 AD 患者和该疾病的动物模型在正常生理状态下通常会受到干扰。在某些情况下，线粒体对于能量代谢至关重要，但在疾病状态下，线粒体在 AD 中，线粒体变得效率低下，氧化应激增加，细胞损伤是不可避免的。失调并变得越来越不正常，昼夜节律也受到干扰。事实上，AD 患者对线粒体的影响很大，核受体 REV-ERB 是一个关键的受体。昼夜节律的转录调节因子，已被证明可以控制线粒体功能和能量因此，我们研究 REV-ERB 是生物能量学的关键调节因子，因此，药理学激活可用于控制线粒体功能并防止细胞能量为此，本文提出的研究旨在1）阐明分子机制。 REV-ERB 用于调节线粒体功能和 2) 确定药理功效激活 REV-ERB 作为针对 AD 临床前模型中生物能缺陷的治疗策略。我们预测这些研究将增进我们对大脑中 REV-ERB 功能的理解，并提供为治疗阿尔茨海默病的新治疗策略奠定了基础。