The role of ketogenic diet metabolites in molecular signaling within distinct brain cell populations.

项目摘要 大脑表现出相当大的能量需求，消耗高达总卡路里摄入量的20%。 首先，成年人的大脑通过分解碳水化合物获得了绝大部分的能量。这个 大脑老化和阿尔茨海默氏症患者利用碳水化合物作为能量来源的能力降低 FDG-PET研究表明，疾病(AD)困扰着大脑。碳水化合物利用率的下降是一种 阿尔茨海默病的早期临床前改变，并可能成为减缓或防止疾病进展的可行的治疗靶点。 这一不足可以通过用一种替代能源来替代大脑来纠正。大脑很容易就会 在某些情况下分解代谢酮体以产生能量。通常情况下，酮体只是 在成人持续限制卡路里期间或维持高热量饮食时产生的 脂肪和低碳水化合物含量。这些所谓的生酮饮食在印度已经使用了近一个世纪。 治疗顽固性癫痫的诊所。此外，一项随机对照试验已经证明 生酮饮食对改善AD患者认知功能的部分疗效。而当 生酮饮食对人类的神经系统有好处，但其作用机制尚不清楚。这个 本提案试图解释生酮饮食及其主要代谢物、脂肪和酮体、 在不同的脑细胞群中影响中枢神经系统的分子信号通路。 我们假设神经元优先利用酮体作为能量来源和备用脂肪 星形胶质细胞的情况正好相反。我们进一步假设这些代谢物会进一步影响 通过改变生物能通量和基因转录的细胞内信号通路。对于我们的第一个目标，我们计划 为了评估初级神经系统细胞系如何对脂肪酸和 酮体。这一目标将通过原代培养产生的神经元和星形胶质细胞在体外进行测试。 从胚胎大鼠前脑和活体通过从成年小鼠脑中分离不同类型的细胞 FACS技术。我们的第二个目标将利用一种表现出结构性酮体生成的转基因小鼠系 在没有饮食操控的情况下，检查脑酮持续给药的效果。这种方法 将使我们能够在不产生混淆变量的情况下检查酮小体对大脑的体内影响 通过使用生酮饮食介绍。这项研究的广泛、长期目标是进一步 阐明大脑如何利用特定脑细胞群体中的生物能量底物。这包括 明确生酮疗法对阿尔茨海默病和癫痫的益处机制以更好地靶向新分子 在治疗这些疾病和改善患者生活方面的途径。

Project Summary The brain exhibits considerable energy demand and consumes as much as 20% of total caloric intake. Primarily, the adult brain acquires the vast majority of its energy through the breakdown of carbohydrates. The capacity to utilize carbohydrates as an energy source is reduced during brain aging and in the Alzheimer's disease (AD) afflicted brain as evidenced by FDG-PET studies. This decline in carbohydrate utilization is an early preclinical change in AD and may be a viable therapeutic target to slow or prevent disease progression. This shortfall may be corrected by substituting an alternative energy source for the brain. The brain will readily catabolize ketone bodies for energy production in certain circumstances. Typically, ketone bodies are only produced in the adult human during periods of sustained caloric restriction or when maintained on a diet high in fat and low in carbohydrate content. These so-called ketogenic diets have been in use for nearly a century in the clinic for the treatment of intractable epilepsy. Additionally, a randomized control trial has demonstrated some efficacy for the ketogenic diet in improving cognitive performance in patients with AD. While the ketogenic diet has neurologic benefit in humans, its mechanism of action remains poorly understood. The present proposal seeks to explain how the ketogenic diet and its primary metabolites, fats and ketone bodies, influence molecular signaling pathways in the central nervous system in distinct brain cell populations. We hypothesize that neurons preferentially utilize ketone bodies as an energy source and spare fats with the reverse being true of astrocytes. We further hypothesize that these metabolites further influence intracellular signaling pathways by altering bioenergetic flux and gene transcription. For our first aim, we plan to assess how primary nervous system cell lines respond bioenergetically to the presence of fatty acids and ketone bodies. This aim will be tested in vitro through primary cultures of neurons and astrocytes generated from embryonic rat forebrain and in vivo through the isolation of distinct cell types from adult mouse brain using FACS technology. Our second aim will make use of a transgenic mouse line exhibiting constitutive ketogenesis in the absence of dietary manipulation to examine the effects of sustained brain ketone delivery. This approach will allow us to examine the in vivo effects of ketone bodies on the brain without creating confounding variables introduced by the use of the ketogenic diet. The broad, long-term objective of this research is to further elucidate how the brain utilizes bioenergetics substrates in specific brain cell populations. This includes defining the mechanism of benefit of ketogenic therapies in AD and epilepsy to better target novel molecular pathways in the treatment of these pathologies and improve patient lives.