GLUCOSE METABOLISM AND THE DEFAULT MODE NETWORK IN HEALTH AND DISEASE

健康和疾病中的葡萄糖代谢和默认模式网络

• 批准号: 8564137
• 负责人: MARCUS E RAICHLE
• 金额: $ 124.94万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8564137
• 关键词: Accounting; Adult; Age; Alzheimer' s Disease; Alzheimer' s disease risk; Area; Brain; Chronic; Deposition; Diabetes Mellitus; Disease; Dorsal; Exhibits; Functional Magnetic Resonance Imaging; Glucose; Glycolysis; Goals; Health; Hyperglycemia; Individual; Insulin Resistance; Lateral; Link; Medial; Molecular; Neurosciences; Non-Insulin-Dependent Diabetes Mellitus; Oxidative Phosphorylation; Parietal; Parietal Lobe; Pathogenesis; Patients; Pattern; Performance; Play; Populations at Risk; Positron-Emission Tomography; Predisposition; Prefrontal Cortex; Research; Rest; Risk Factors; Role; Signal Transduction; Sleep; Sleep Deprivation; System; Temporal Lobe; Testing; Work; blood glucose regulation; glucose metabolism; insulin sensitivity; interest; programs; public health relevance; research study

DESCRIPTION (provided by applicant): The overarching hypothesis in this proposal is that brain glucose metabolism outside of oxidative phosphorylation (which we refer to as glycolysis) plays an important role in brain function in health and disease. Our interest in glycolysis arose from several observations made by us leading up to this proposal. Glycolysis accounts for 12 to15% of glucose metabolized by the adult human brain. A large fraction of this glycolysis occurs in a network of brain areas dubbed the brain's default mode network (DMN). The DMN consists of areas in medial and lateral parietal cortices, dorsal and ventral medial prefrontal cortex and the medial temporal cortices. It is noteworthy because it is more active in the resting state, is central to the functional organization of the brain, has the highest rate of glycolysis o any group of brain areas and is uniquely vulnerable to Alzheimer's disease. Because diabetes has emerged as a significant risk factor for Alzheimer's disease caused us to consider these two diseases together in terms of how glucose metabolism might not only serve to define a specific network of areas in the brain but also increase the vulnerability of these areas to Alzheimer's disease. In the experiments proposed, we ask how brain glycolysis and resting-state functional connectivity are regulated by age, sleep and systemic alterations in glucose homeostasis and insulin sensitivity. We specifically hypothesize that chronic hyperglycemia and insulin resistance as well as sleep deprivation increase glycolysis and A¿ release in brain areas, such as the DMN, that are heavily reliant on glycolysis, leading to increased A¿ deposition and accelerating the pathogenesis of AD. Project 1 and 2 will explore how brain glycolysis and functional connectivity in the DMN are regulated by systemic alterations in glucose homeostasis and insulin sensitivity in populations at risk for AD (older individuals and people with T2DM), and experiments in Project 3 will enable ideas tested in Projects 1 and 2 to be taken from the systems neuroscience level to the cellular and molecular level.

描述（由申请人提供）：该提案的总体假设是，氧化磷酸化（我们称为糖酵解）之外的脑葡萄糖代谢在健康和疾病的脑功能中发挥着重要作用。我们对糖酵解的兴趣源于多项观察。糖酵解占成人大脑代谢葡萄糖的 12% 至 15%，其中很大一部分发生在被称为“大脑区域”的网络中。大脑的默认模式网络（DMN）由内侧和外侧顶叶皮质、背侧和腹侧内侧前额皮质以及内侧颞叶皮质组成，它在静息状态下更加活跃，是大脑的中心。大脑的功能组织，在所有大脑区域中糖酵解率最高，并且特别容易患阿尔茨海默病，因为糖尿病已成为导致我们患阿尔茨海默病的一个重要危险因素。将这两种疾病放在一起考虑，葡萄糖代谢不仅可以定义大脑中特定的区域网络，而且还增加这些区域对阿尔茨海默氏病的脆弱性。状态功能连接受到年龄、睡眠以及葡萄糖稳态和胰岛素敏感性的系统改变的调节，我们特别认为慢性高血糖和胰岛素抵抗以及睡眠不足会增加糖酵解和A¿大脑区域（例如DMN）的释放，这些区域严重依赖糖酵解，导致A¿项目 1 和 2 将探索 AD 风险人群（老年人和 T2DM 患者）中葡萄糖稳态和胰岛素敏感性的系统性改变如何调节 DMN 中的脑糖酵解和功能连接，以及 项目 3 中的实验将使项目 1 和 2 中测试的想法能够从系统神经科学水平扩展到细胞和分子水平。