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Pyruvate and acetate metabolism after TBI: implications for cerebral energy metabolism

TBI 后丙酮酸和乙酸代谢：对脑能量代谢的影响

基本信息

批准号：
10250001
负责人：
Jae Mo Park
金额：
$ 56.37万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10250001
关键词：
Acetates Acetyl Coenzyme A Acute Affect Age Animals Astrocytes Bicarbonates Bioenergetics Brain Brain Injuries Carbon Carbon Dioxide Cell Respiration Cerebrum Cessation of life Citric Acid Cycle Clinical Closure by clamp Complex Data Disease Early Diagnosis Early Intervention Energy Metabolism Enzymes Equilibrium Event Failure Fatty Acids Freezing Functional disorder Glasgow Coma Scale Glucose Glutamates Glutamine Glycolysis Goals Head Human Image Imaging Device Impairment Individual Infusion procedures Injury Ketones Label Measurement Measures Mechanics Metabolic Metabolic Pathway Metabolism Mitochondria Modeling Neurological outcome Neurons Neurotransmitters Nodal Non-Invasive Cancer Detection Oxidative Phosphorylation Pathologic Pathway interactions Patient imaging Patient-Focused Outcomes Patients Play Process Production Pyruvate Pyruvate Carboxylase Pyruvate Metabolism Pathway Rattus Role Scanning TBI treatment Techniques Therapeutic Therapeutic Intervention Time Tissue Extracts Tissues Translating Traumatic Brain Injury Tricarboxylic Acids Unconscious State brain tissue carboxylation clinical imaging disability effective therapy follow-up glucose metabolism high risk imaging modality improved in vivo in vivo imaging magnetic resonance spectroscopic imaging metabolic imaging mild traumatic brain injury noninvasive diagnosis oxidation personalized medicine potential biomarker prevent pyruvate dehydrogenase real-time images recruit spectroscopic imaging

项目摘要

A major challenge of treating traumatic brain injury (TBI) patients is the simultaneously occurring complex secondary injury processes following the primary injury. The secondary events such as cerebral hyperglycolysis and mitochondrial failure develop over minutes to months after the primary injury, providing a potential window of opportunity for therapeutic intervention. Given early, this intervention may prevent or reduce secondary brain damage, directly impacting long-term patient outcome. Therefore, the noninvasive detection and characterization of pathophysiology in TBI patients during the acute and early sub-acute stages, will have critical clinical implications for the early diagnosis of individuals with the highest risk of poor neurological outcomes and will be vital for identifying and developing effective therapies. While a number of pathological alternations in TBI are potential biomarkers, no current clinical imaging modalities are sensitive enough to be routinely used to detect the details of metabolic shifts in brain sub-regions with secondary injury. Magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized 13C-labeled substrates provides unique noninvasive measurements of critical in vivo dynamic metabolic processes. In particular, pyruvate occupies a key nodal point in cerebral energy metabolism, among the fates of [1-13C]pyruvate are reduction to lactate as the end product of glycolysis, conversion in mitochondria to form acetyl-CoA and CO2 (detected as HCO3–) via pyruvate dehydrogenase (PDH) flux or anaplerotic pyruvate carboxylase (PC) pathway for oxidative phosphorylation. [2-13C]pyruvate, on the other hand, directly assess the tricarboxylic acid (TCA) cycle by detecting [5-13C]glutamate production. While our preliminary data demonstrated increased lactate and decreased HCO3– (bicarbonate) production from hyperpolarized [1-13C]pyruvate in a rat TBI model and acute TBI patients, however, the role of [13C]HCO3– as a TCA cycle marker needs further verification due to the high pyruvate carboxylation. Another key metabolic alteration following TBI is increased acetate oxidation in astrocytes, playing a neuro-protective role. The increased acetate metabolism tightly interacts with pyruvate metabolism, and thus, should be considered together when interpreting [13C]pyruvate metabolism. The fundamental goal of this project is to understand how TBI influences the in vivo cellular metabolism in the brain using hyperpolarized 13C MRSI as a step towards personalizing therapy for TBI patients. In this proposal, a comprehensive analysis of TBI metabolism will be performed using a rat TBI model by comparing the in vivo imaging results with ex vivo tissue analysis. First, we will develop hyperpolarized [2-13C]pyruvate as a probe to directly measure the altered TCA cycle activity in TBI (aim 1). Second, we will assess the contribution of increased acetate metabolism to pyruvate oxidation in a rat TBI model (aim 2). The longitudinal in vivo imaging data (aims 1&2) will be validated by cross-sectional ex vivo NMR isotopomer analysis of freeze-clamped brain tissues. Finally, we will translate the technique to assess metabolic changes in acute mild TBI patients (aim 3).

治疗创伤性脑损伤（TBI）患者的一个主要挑战是同时发生的复杂性，原发性损伤后的继发性损伤。继发性事件，如脑在原发性损伤后数分钟至数月内，糖酵解过度和线粒体功能衰竭发生，治疗干预的潜在机会窗口。如果及早采取干预措施，减少继发性脑损伤，直接影响患者的长期预后。因此，非侵入性 TBI患者在急性和早期亚急性阶段的病理生理学检测和表征，将对患有最高风险的穷人的早期诊断具有重要的临床意义。神经系统的结果，并将是至关重要的识别和开发有效的治疗方法。虽然一些 TBI的病理改变是潜在的生物标志物，目前没有敏感的临床成像方式足以常规用于检测继发性损伤的大脑亚区域中代谢变化的细节。超极化13 C标记底物的磁共振光谱成像（MRSI）提供了独特的关键的体内动态代谢过程的非侵入性测量。特别地，丙酮酸占据了脑能量代谢的关键节点，[1- 13 C]丙酮酸的命运是还原为乳酸，糖酵解的终产物，在线粒体中转化形成乙酰辅酶A和CO2（检测为HCO 3-），丙酮酸脱氢酶（PDH）通量或回补丙酮酸羧化酶（PC）途径用于氧化磷酸化另一方面，[2- 13 C]丙酮酸盐通过以下方式直接评估三羧酸（TCA）循环：检测[5- 13 C]谷氨酸的产生。虽然我们的初步数据显示乳酸盐增加，在大鼠TBI模型和急性TBI中，超极化[1- 13 C]丙酮酸盐的HCO 3-（碳酸氢盐）产生减少然而，TBI患者中，[13 C] HCO 3-作为TCA循环标志物的作用需要进一步验证，因为[13 C] HCO 3-的高浓度，丙酮酸羧化TBI后的另一个关键代谢改变是TBI中乙酸盐氧化增加。星形胶质细胞，发挥神经保护作用。增加的乙酸代谢与丙酮酸密切相互作用因此，在解释[13 C]丙酮酸代谢时应一并考虑。该项目的基本目标是了解TBI如何影响体内细胞代谢，脑使用超极化13 C MRSI作为TBI患者个性化治疗的一步。在这项提案中，将使用大鼠TBI模型，通过比较体内TBI代谢，离体组织分析的成像结果。首先，我们将开发超极化[2- 13 C]丙酮酸作为探针，直接测量TBI中改变的TCA循环活性（目的1）。第二，我们将评估在大鼠TBI模型中增加乙酸盐代谢为丙酮酸盐氧化（目的2）。纵向活体成像数据（目标1和2）将通过冷冻夹持脑的横截面离体NMR同位素异构体分析进行验证组织中最后，我们将把这项技术用于评估急性轻度TBI患者的代谢变化（目的3）。