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，消耗高达总热量摄入的20%。 首先，成年人的大脑通过分解碳水化合物获得绝大多数能量。的 在大脑衰老和阿尔茨海默氏症期间，利用碳水化合物作为能源的能力会降低 FDG-PET研究证实了患有AD的大脑。这种碳水化合物利用率的下降是一种 AD的早期临床前变化，可能是减缓或预防疾病进展的可行治疗靶点。 这种不足可以通过替代大脑的替代能源来纠正。大脑会很容易地 在某些情况下分解代谢酮体以产生能量。通常，酮体仅 在持续的热量限制期间或当维持高热量饮食时， 脂肪和低碳水化合物含量。这些所谓的生酮饮食已经使用了近世纪， 难治性癫痫的临床治疗。此外，一项随机对照试验表明， 生酮饮食在改善AD患者的认知能力方面具有一定的功效。而 生酮饮食在人类中具有神经学益处，但其作用机制仍知之甚少。的 本发明试图解释生酮饮食及其初级代谢物，脂肪和酮体， 影响中枢神经系统中不同脑细胞群的分子信号通路。 我们假设神经元优先利用酮体作为能量来源，而不消耗脂肪 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进一步影响 通过改变生物能流和基因转录来调节细胞内信号传导途径。我们的第一个目标是， 为了评估原代神经系统细胞系如何对脂肪酸的存在作出生物能量响应， 酮体。这一目标将在体外通过神经元和星形胶质细胞的原代培养进行测试， 从胚胎大鼠前脑和体内通过分离不同的细胞类型从成年小鼠脑， FACS技术。我们的第二个目标是利用表现出组成性酮生成的转基因小鼠品系 在没有饮食控制的情况下，检查持续脑酮递送的影响。这种方法 将使我们能够检查酮体对大脑的体内影响，而不会产生混淆变量 是通过生酮饮食引入的。这项研究的广泛和长期目标是进一步 阐明大脑如何利用特定脑细胞群中的生物能量学底物。这包括 明确生酮疗法在AD和癫痫中的获益机制，以更好地靶向新分子 治疗这些疾病的途径，并改善患者的生活。

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.