Pyruvate dehydrogenase encephalopathy: mechanisms and therapy

丙酮酸脱氢酶脑病：机制和治疗

基本信息

批准号：
10225409
负责人：
Juan M. Pascual
金额：
$ 35.44万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10225409
关键词：
Acetates Acetyl Coenzyme A Address Beds Biochemical Biochemistry Biological Assay Brain Brain Diseases Carbon Caring Cell Culture Techniques Cerebral cortex Cerebrum Child Citric Acid Cycle Clinical Clinical Trials Consumption Data Development Dietary Fats Disease Disease model Disorder of neurometabolic regulation Electrodes Electroencephalography Electrophysiology (science)Encephalopathies Energy Metabolism Equilibrium Fatty Acids Fatty acid glycerol esters Food Functional disorder Generations Genes Glucose Glutamates Glycolysis Goals Health Human Impairment In Vitro Infant Intellectual functioning disability Investigation Ketone Bodies Ketones Knowledge Label Laboratories Lead Life Medical Metabolic Metabolic Diseases Metabolic dysfunction Metabolism Mission Modeling Motor Mus Mutation NMR Spectroscopy Neuroglia Neurologic Dysfunctions Neurons Neurophysiology - biologic function Neurotransmitters Patients Performance Pharmaceutical Preparations Process Reaction Refractory Resources Seizures Sensory Slice System Testing Therapeutic Thick Tricarboxylic Acids United States National Institutes of Health Work awake base brain metabolism brain tissue clinical investigation cohort dietary disabling disease epileptic encephalopathies gamma-Aminobutyric Acid in vivo in vivo evaluation intervention effect ketogenic diet liver metabolism mouse model neocortical neural circuit novel novel therapeutics optogenetics palliative prenatal preservation prevent programs pyruvate dehydrogenase relating to nervous system synaptic function therapeutic development virtual

项目摘要

ABSTRACT This proposal constitutes one of the first mechanistic investigations of pyruvate dehydrogenase (PDH) deficiency encephalopathy (PDHD), an inborn developmental brain disorder. PDHD leads to impaired brain metabolism and neurological dysfunction that manifests as intellectual disability and intractable seizures in infants and children. The elementary biochemical framework has been elucidated primarily in vitro using cell cultures and homogenates. Normally PDH receives about 80% of the brain’s glucose metabolic flux, converting it into substrate for the tricarboxylic acid (TCA) cycle. The TCA cycle is responsible for brain energy generation and also for the synthesis of the neurotransmitters glutamate and GABA, which regulate excitability. The remainder 20% of brain glucose refills natural TCA cycle precursor loss, which is accomplished through a separate process known as anaplerosis. Yet, anaplerosis can also be secondarily downregulated in PDHD. Nevertheless, despite these long-established biochemical principles, it is unknown how PDHD causes encephalopathy. In particular, very little is known about metabolism or excitability within PDHD brain tissue and even less is known in an in vivo context. This knowledge gap drastically limits therapy, as illustrated by the drug-refractoriness of PDHD seizures. The objectives of this application are to characterize in vivo abnormal neural excitability and metabolism in a novel, robust PDHD mouse model and to mitigate them by stimulating both the TCA cycle and anaplerosis with alternative dietary substrates. Our preliminary results include abnormal neocortical excitability in PDHD in vivo and amelioration of brain TCA cycle precursor depletion, and thus justify investigating these mechanisms in greater depth. This leads to a first general hypothesis that metabolic fuel-dependent (rather than fixed) cortical dysfunction is a central feature of disease pathophysiology. The proposal also includes the therapeutic consideration that ketone bodies containing an even number of carbons, generated from common dietary fats or a ketogenic diet, can fuel the TCA cycle and ameliorate seizures in PDHD patients, but cannot correct anaplerotic deficits. In contrast, our data that exogenous anaplerotic fat metabolites containing an odd number of carbons can additionally refill brain TCA cycle precursors, lead to a second general hypothesis: That odd-carbon fat restores neural function in PDHD more effectively via anaplerosis than even-carbon fat. These two general hypotheses will be tested in three aims: 1) Investigate the electrophysiological bases of cortical hyperexcitability in PDHD; 2) Test key metabolic mechanisms relevant to synaptic function; 3) Restore brain metabolism and excitability via anaplerotic odd-carbon fat derivatives. In summary, we expect to help define PDHD as an excitability disorder and establish the therapeutic value of anaplerotic modulation, thus initiating the first step of a medical practice transformation by capitalizing on metabolic or excitable targets.

抽象的该建议构成了丙酮酸脱氢酶（PDH）缺乏的首次机械研究之一脑病（PDHD），一种天生的发育性脑部疾病。 PDHD导致脑代谢受损以及在婴儿和孩子们。基础生化框架已主要使用细胞培养物在体外阐明，匀浆。通常PDH会收到大脑的葡萄糖代谢通量的80％，将其转换为三核酸（TCA）周期的底物。 TCA周期负责大脑能量产生和还用于合成调节令人兴奋性的神经递质谷氨酸和GABA。其余的 20％的脑葡萄糖补充天然TCA循环前体损失，这是通过单独的过程完成的被称为衰减。然而，在PDHD中，旋律也可以次要下调。然而，dospite 这些长期以来的生化原则，PDHD如何引起脑病是未知的。尤其，关于PDHD脑组织内的新陈代谢或兴奋性知之甚少，甚至更少体内上下文。 PDHD的药物不良性说明了这些知识差距极大地限制了治疗癫痫发作。该应用程序的目标是表征体内异常神经令人兴奋和新颖，强大的PDHD小鼠模型中的代谢，并通过刺激TCA循环和替代饮食底物的无稳固性。我们的初步结果包括异常的新皮质激动人心在PDHD体内和脑TCA周期前体部署的改善，从而证明研究了这些更深入的机制。这导致了一个普遍的假设，即代谢燃料依赖性（而不是固定）皮质功能障碍是疾病病理生理学的主要特征。该提案还包括治疗性考虑的是，酮体含有均匀数量的碳，由普通产生饮食脂肪或生酮饮食，可以为PDHD患者的TCA周期和癫痫发作增强，但不能纠正变性缺陷。相比之下，我们的数据外源性无蛋白脂肪代谢产物含有奇数碳数量可以另外补充脑TCA循环前体，导致第二个一般假设：奇怪脂肪比均匀脂肪更有效地通过无氧脂肪恢复PDHD中的神经功能。这些两个总体假设将在三个目的中进行测试：1）研究皮质的电生理基础 PDHD中的过度兴奋性； 2）测试与突触功能相关的关键代谢机制； 3）恢复大脑通过变性奇怪脂肪衍生物的代谢和兴奋。总而言之，我们希望有助于定义 PDHD是一种令人兴奋的疾病，并建立了旋律调节的治疗价值，因此启动医疗实践转型的第一步是利用代谢或令人兴奋的目标。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mitochondrial disease manifestations in relation to transcriptome location and function.

DOI：
10.1016/j.ymgme.2021.12.008
发表时间：
2022-01
期刊：
Molecular genetics and metabolism
影响因子：
3.8
作者：
Jakkamsetti V;Balasubramaniam S;Grover N;Pascual JM
通讯作者：
Pascual JM

Quantification of early learning and movement sub-structure predictive of motor performance.

DOI：
10.1038/s41598-021-93944-9
发表时间：
2021-07-13
期刊：
Scientific reports
影响因子：
4.6
作者：
Jakkamsetti V;Scudder W;Kathote G;Ma Q;Angulo G;Dobariya A;Rosenberg RN;Beutler B;Pascual JM
通讯作者：
Pascual JM

Development and validation of a LC-MS/MS method for quantitation of 3-hydroxypentanoic acid and 3-oxopentanoic acid in human plasma and its application to a clinical study of glucose transporter type I deficiency (G1D) syndrome.

DOI：
10.1016/j.jpba.2021.114335
发表时间：
2021-10-25
期刊：
Journal of pharmaceutical and biomedical analysis
影响因子：
3.4
作者：
Kallem RR;Primeaux S;Avila A;Pascual JM;Putnam WC
通讯作者：
Putnam WC

Author Correction: Quantification of early learning and movement sub-structure predictive of motor performance.

DOI：
10.1038/s41598-021-99461-z
发表时间：
2021-09-29
期刊：
Scientific reports
影响因子：
4.6
作者：
Jakkamsetti V;Scudder W;Kathote G;Ma Q;Angulo G;Dobariya A;Rosenberg RN;Beutler B;Pascual JM
通讯作者：
Pascual JM