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

• 批准号: 10487464
• 负责人: Jae Mo Park
• 金额: $ 55.61万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 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/10487464
• 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

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）患者的主要挑战是同时发生的复合体