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（由适用提供）：该提案中的总体假设是，氧化磷酸化之外的脑葡萄糖代谢（我们称为糖酵解）在大脑功能中在健康和疾病中起重要作用。我们对糖酵解的兴趣源于我们在提出这一提议之前的几种观察结果。糖酵解占成年人脑代谢的葡萄糖的12％至15％。这种糖酵解的很大一部分发生在一个称为大脑默认模式网络（DMN）的大脑区域网络中。 DMN由媒体和侧面巴由皮层，背侧和腹介质前额叶皮层以及媒体临时皮质组成。值得注意的是，它在静息状态更为活跃，是大脑功能组织的核心，其糖酵解的速率最高，并且任何脑部的大脑区域均具有最高的作用，并且非常容易受到阿尔茨海默氏病的影响。因为糖尿病已成为阿尔茨海默氏病的重要危险因素，这使我们从葡萄糖代谢如何使用这两种疾病中考虑了这两种疾病，这不仅可能有助于定义大脑中特定的地区网络，而且增加了这些地区对阿尔茨海默氏病的脆弱性。在提出的实验中，我们询问脑糖酵解和静止状态功能连通性如何受到葡萄糖稳态和胰岛素敏感性的年龄，睡眠和全身改变的调节。我们特别假设慢性高血糖和胰岛素抵抗以及睡眠剥夺增加了糖酵解和在大脑区域（例如DMN）的释放，这些脑区域（例如DMN）在很大程度上依赖于糖酵解，从而导致A s降低和加速AD的病原体。项目1和2将探讨DMN中脑糖酵解和功能连通性如何受到葡萄糖稳态的全身性改变和对AD风险（老年人和T2DM患者）和患者的胰岛素敏感性的全身改变和胰岛素敏感性的调节。 项目3中的实验将使项目1和2中测试的想法从系统神经科学水平到细胞和分子水平进行。