Translational assessment of brain bioenergetic function in schizophrenia

精神分裂症大脑生物能量功能的转化评估

• 批准号: 10532752
• 负责人: Christopher Marano
• 金额: $ 71万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532752
• 关键词: Affect; Age; Animal Model; Anterior; Antipsychotic Agents; Astrocytes; Autopsy; Biochemical; Bioenergetics; Bioinformatics; Biological; Biological Assay; Blood; Brain; Brain imaging; Brain region; Caring; Cell Line; Cells; Clinical; Clinical assessments; Coculture Techniques; Cognition; Cognitive; Complement; Coupled; Data; Defect; Delusions; Development; Dopamine Antagonists; Dopamine D2 Receptor; Energy Metabolism; Enzymes; Failure; Functional disorder; Generations; Genetic; Glucose; Goals; Hallucinations; Human; Image; Impaired cognition; Impairment; Induced pluripotent stem cell derived neurons; Intervention; Lasers; Magnetic Resonance Spectroscopy; Medical; Metabolic; Metabolism; Methods; Microdissection; Molecular; Neurobehavioral Manifestations; Neuronal Plasticity; Neurons; Occipital lobe; Outcome Assessment; Oxidative Phosphorylation; Pathologic; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacological Treatment; Population; Production; Protons; Quality of life; Reporting; Sampling; Schizophrenia; Symptoms; Thalamic structure; Tissues; Wages; Work; brain dysfunction; cell type; cingulate cortex; cognitive function; cost; functional outcomes; glucose uptake; improved; in silico; induced pluripotent stem cell; neuroimaging; neuron development; novel therapeutic intervention; severe mental illness; sex; therapy development; tissue culture; translational approach; uptake

Project Summary Schizophrenia is a devastating illness with no cure, affecting about 1% of the population worldwide, costing billions of dollars annually. The scientific premise for this proposal is based on accumulating imaging, postmortem, animal model, genetic, and bioinformatics data converging on alterations in the production of bioenergetic molecules in myriad brain regions in this illness. We previously reported abnormally high levels of lactate in living patients with schizophrenia that were strongly associated with poor cognitive function. This finding complements our induced pluripotent stem cell (iPSC) and postmortem work showing higher lactate levels in schizophrenia in iPSC-derived cortical neurons and postmortem anterior cingulate cortex in subjects with schizophrenia. Based on this evidence, we hypothesize that diminished cognitive functioning in schizophrenia is due to impaired bioenergetic metabolism in limbic circuits with increased pathological generation or utilization of lactate in schizophrenia. Specifically, we posit that there is increased production and release of lactate from astrocytes, coupled with increased uptake and utilization of lactate, in lieu of glucose uptake and oxidative phosphorylation, to produce ATP in support of neuronal plasticity in limbic circuits. This new R01 project uses complementary, but distinct approaches, to examine abnormalities of bioenergetic function in schizophrenia. For SA1, we will use magnetic resonance spectroscopy (MRS) to quantify lactate levels and comprehensively characterize patients using neuroimaging, clinical, cognitive, functioning, and metabolic assessments. For Aim 2, cultured human neurons/astrocytes derived from iPSCs obtained in SA1 to assess lactate production and utilization challenges. We will further delineate the functional consequences of lactate production on cellular energy metabolism and neuronal development/function at molecular and cellular levels in cultured human iPSC-derived neurons/astrocytes. In Aim 3, we will use a bioinformatics approach to identify lactate-associated targets for cell-subtype specific studies of biochemical/lactate changes in postmortem brain. Taken together, our aims will comprehensively assess perturbations of lactate and lactate associated pathways across clinical, tissue culture, and postmortem substrates in schizophrenia. By developing a more sophisticated understanding of the pathophysiology of schizophrenia, this project will help identify targets in bioenergetic pathways for development of treatment interventions for this debilitating illness.

项目摘要 精神分裂症是一种毁灭性疾病，无法治愈，影响了全球约1％的人口 每年数十亿美元。该提案的科学前提是基于累积成像， 验尸，动物模型，遗传和生物信息学数据收敛于生产的改变 在这种疾病中，无数大脑区域的生物能分子。我们以前报道了异常高水平的 精神分裂症患者的乳酸与认知功能差密切相关。这 发现我们诱导的多能干细胞（IPSC）和验尸作品显示较高的乳酸 IPSC衍生的皮质神经元中精神分裂症的水平和受试者前扣带回皮质的水平 精神分裂症。基于这些证据，我们假设在 精神分裂症是由于病理学增加而导致的生物能代谢受损 精神分裂症中乳酸的产生或利用。具体来说，我们认为生产增加 并从星形胶质细胞中释放乳酸，再加上乳酸的摄取和利用率增加，代替 葡萄糖的摄取和氧化磷酸化，以支持ATP，以支持边缘的神经元可塑性 电路。这个新的R01项目使用互补但不同的方法来检查异常 精神分裂症中的生物能功能。对于SA1，我们将使用磁共振光谱（MRS）到 量化乳酸水平，并全面地使用神经成像，临床，认知，认知， 功能和代谢评估。对于AIM 2，源自IPSC的培养的人类神经元/星形胶质细胞 在SA1中获得以评估乳酸生产和利用挑战。我们将进一步描述功能 乳酸产生对细胞能量代谢和神经元发育/功能的后果 培养的人IPSC衍生的神经元/星形胶质细胞中的分子和细胞水平。在AIM 3中，我们将使用 生物信息学方法以鉴定与乳酸相关的靶标，以用于细胞型的特定研究 验尸大脑的生化/乳酸变化。综上所述，我们的目标将全面评估 乳酸和乳酸相关途径跨临床，组织培养和死后的扰动 精神分裂症中的底物。通过对病理生理的更复杂的理解 精神分裂症，该项目将有助于确定生物能途径中的目标 这种使人衰弱的疾病的干预措施。