Brain glucose deficiency: mechanisms and modulation

脑葡萄糖缺乏：机制和调节

• 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
• 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

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.

脑部葡萄糖缺乏症：机制和调节。摘要 生化原理、实验和临床观察支持糖代谢的中心性 对大脑功能的影响。在此背景下，诊断正电子发射断层扫描应用于几类 神经疾病，如痴呆症或癫痫，长期以来明显减少了葡萄糖的积累 在特定的大脑区域。然而，这并不一定等同于下游的类似削减 代谢流量和神经兴奋。事实上，内源性的替代燃料和过度兴奋通常是 在这些疾病中观察到的。在这项提案中，我们将开发代谢和神经生理学方法来 用葡萄糖转运蛋白I(GLUT1)缺乏(G1D)作为模型来阐明这一明显的兴奋性悖论 系统。概念框架基于适用于越来越多的障碍的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)这些机制可以非侵入性地在患者身上观察到；3) 它们可能被新陈代谢调节以获得治疗收益。为了测试这些假设，我们将首先描述 G1D小鼠模型中代谢和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流量 人。团队方法将协调整个生物领域的机制和结果的进展 从分子通量和相互转化到细胞的尺度，丘脑皮质回路，行为小鼠和 人类的大脑。团队是不可或缺的，因为我们的每个调查目标都通过超过 我们的一个实验室，从每种实验方法获得的结果通知其余的研究。 因为这些方法对通量比简单的丰度更敏感，所以我们将评估两种通量 描述G1D大脑整体神经生理和代谢状态的比率：1)LGR(低到伽马 频率电振荡比)和2)GOI(血糖氧化脑TCA循环指数)。 翻译将通过一项基本的人类实验研究来实现，该研究将测试GOI是否反映 疾病的严重性。我们将在利用机制测试的机械试验中进一步测试GOI和LGR 广泛适用于代谢干预的框架。该试验将调查红细胞交换(即， 用健康供体细胞替代缺乏GLUT1的人G1D循环红细胞 增强血液到大脑葡萄糖转运的新方法。该提案得益于结构化管理， 用于增强利用和扩展的不同视角和数据共享的计时基准和计划 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 和方法学基础，以转变对其他丘脑皮质疾病的评估或治疗评估 痴呆和癫痫类型的代谢障碍和代谢治疗的机制分析。