Brain glucose deficiency: mechanisms and modulation

脑葡萄糖缺乏：机制和调节

基本信息

批准号：
10730183
负责人：
Stuart F Cogan
金额：
$ 178.24万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10730183
关键词：
Area Benchmarking Biochemical Biological Biological Models Blood Blood Glucose Brain Brain imaging Categories Cells Citric Acid Cycle Clinical Clinical Trials Clinical Trials Design Cognition Cognitive Data Dementia Deoxyglucose Development Diagnostic Disease Electrocorticogram Electroencephalography Epilepsy Equilibrium Erythrocytes Evaluation Exhibits Failure Florida Foundations Frequencies Functional disorder Generations Genetic Models Glucose Glucose Transporter Glutamates Glycogen Glycoproteins Health Human In Vitro Inhibitory Synapse Institution Intervention Intractable Epilepsy Ketone Bodies Laboratories Legal patent Locomotion Magnetic Resonance Imaging Mass Spectrum Analysis Measurement Measures Metabolic Metabolic Brain Diseases Metabolic Pathway Metabolism Methodology Methods Mission Molecular Motor Movement Mus Mutation Neuronal Dysfunction Neurons Neurophysiology - biologic function Neurotransmitters Nuclear Magnetic Resonance Outcome Pathogenicity Patient Care Persons Pharmaceutical Preparations Play Polysaccharides Positron-Emission Tomography Resources Rest Schizophrenia Seizures Severities Severity of illness Slice Structure Syndrome Testing Therapeutic Translations United States National Institutes of Health Work beta-Hydroxybutyrate blood fractionation brain endothelial cell brain metabolism clinical investigation comparative data sharing experimental study gamma-Aminobutyric Acid glucose metabolism glucose transport in vivo indexing inhibitory neuron ketogenic diet metabolic depression method development mouse model multidisciplinary nervous system disorder neural neural circuit neurophysiology novel novel therapeutics oxidation public health relevance restoration synaptic failure therapeutic development treadmill

项目摘要

BRAIN GLUCOSE DEFICIENCY: MECHANISMS AND MODULATION. ABSTRACT Biochemical principles and experimental and clinical observations support the centrality of glucose metabolism to brain function. In this context, diagnostic positron emission tomography applied to several categories of neurological disorders such as dementia or epilepsy has long made patent reductions in glucose accumulation in certain brain areas. However, this is not necessarily synonymous with similar reductions in downstream metabolic flux and neural excitation. In fact, endogenous alternative fueling and hyperexcitability are often observed in these diseases. In this proposal, we will develop the metabolic and neurophysiological means to clarify this apparent excitability paradox by using Glucose transporter I (GLUT1) deficiency (G1D) as a model system. The conceptual framework rests on 3 postulates applicable to an increasing number of disorders: 1) metabolic failure results in preferential inhibitory (relative to excitatory) neuron dysfunction, which alters specific neural circuit activities; 2) these mechanisms can be non-invasively observed at play in afflicted persons and 3) they may be metabolically modulated for therapeutic gain. To test the postulates, we will first characterize the interrelation between metabolism and excitability in a G1D mouse model. With this information, we will then measure flux downstream from glucose to neurotransmitters in conjunction with neurophysiological activity in persons. A team approach will harmonize the progression of mechanisms and results across the biological scale spanning from molecular flux and interconversions to cells, the thalamocortical circuit, behaving mice and the human brain. The team is indispensable because each of our investigational aims is fulfilled by more than one of our laboratories, with the results obtained from each experimental method informing the rest of the studies. Because the methods are inherently sensitive to flux rather than simple abundance, we will evaluate two flux ratios that describe the overall neurophysiological and metabolic states of the G1D brain: 1) LGR (low to gamma frequency electrical oscillation ratio) and 2) GOI (blood glucose oxidation by the brain TCA cycle index). Translation will be achieved via a Basic Experimental Study with Humans that will test whether GOI reflects disease severity. We will further test GOI and LGR in a Mechanistic Trial that will utilize a mechanism-testing framework broadly applicable to metabolic interventions. The trial will investigate red blood cell exchange (i.e., the replacement of human G1D circulating red cells, which are deficient in GLUT1) with healthy donor cells as a novel means to augment blood-to-brain glucose transport. The proposal benefits from structured management, timed benchmarks and Plans for Enhancing Diverse Perspectives and Data Sharing that leverage and extend extensive institutional and G1D Foundation resources. If successful, our approach will provide the conceptual and methodological groundwork to transform the evaluation or treatment assessment of other thalamocortical disorders and the mechanistic analysis of metabolic treatments in types of dementia and epilepsy.

脑葡萄糖缺乏：机制和调节。抽象的生化原理以及实验和临床观察支持葡萄糖代谢的中心地位对大脑功能。在此背景下，诊断性正电子发射断层扫描应用于几类痴呆或癫痫等神经系统疾病长期以来一直导致葡萄糖积累明显减少在某些大脑区域。然而，这并不一定等同于下游类似的减少。代谢通量和神经兴奋。事实上，内源性替代燃料和过度兴奋往往是在这些疾病中观察到。在本提案中，我们将开发代谢和神经生理学手段通过使用葡萄糖转运蛋白 I (GLUT1) 缺乏症 (G1D) 作为模型来阐明这种明显的兴奋性悖论系统。该概念框架基于适用于越来越多疾病的 3 个假设：1) 代谢衰竭导致优先抑制性（相对于兴奋性）神经元功能障碍，从而改变特定的神经回路活动； 2) 这些机制可以在患者身上以非侵入性方式观察到，并且 3) 它们可以通过代谢调节以获得治疗效果。为了检验这些假设，我们首先要描述 G1D 小鼠模型中代谢与兴奋性之间的相互关系。有了这些信息，我们将结合神经生理活动测量从葡萄糖到神经递质的下游通量人。团队方法将协调整个生物领域的机制和结果的进展范围从分子流动和相互转换到细胞、丘脑皮层回路、行为小鼠和人类的大脑。这个团队是不可或缺的，因为我们的每一个研究目标都是由超过我们的一个实验室，从每种实验方法获得的结果为其余的研究提供信息。因为这些方法本质上对通量而不是简单的丰度敏感，所以我们将评估两个通量描述 G1D 大脑整体神经生理学和代谢状态的比率：1) LGR（低至伽马）频率电振荡比）和2）GOI（大脑TCA循环血糖氧化指数）。翻译将通过人类基础实验研究来实现，该研究将测试 GOI 是否反映疾病的严重程度。我们将在机制试验中进一步测试 GOI 和 LGR，该试验将利用机制测试框架广泛适用于代谢干预。该试验将调查红细胞交换（即，用健康的供体细胞替代缺乏 GLUT1 的人类 G1D 循环红细胞作为增强血液到大脑葡萄糖转运的新方法。该提案受益于结构化管理，用于增强多元化观点和数据共享的定时基准和计划，以利用和扩展广泛的机构和 G1D 基金会资源。如果成功，我们的方法将提供概念性的以及改变其他丘脑皮质的评估或治疗评估的方法学基础痴呆和癫痫类型的疾病和代谢治疗的机制分析。