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: 10064011
• 负责人: Christopher Marano
• 金额: $ 72.71万
• 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/10064011
• 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; base; brain dysfunction; cell type; cingulate cortex; cognitive function; cost; functional outcomes; glucose uptake; improved; in silico; induced pluripotent stem cell; neuroimaging; neuron development; severe mental illness; sex; therapy development; tissue culture; translational approach; treatment strategy; 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 精神分裂症是一种无法治愈的毁灭性疾病，影响全球约1%的人口， 每年数十亿美元。这项提议的科学前提是基于累积成像， 尸检，动物模型，遗传学和生物信息学数据集中在生产的变化， 在这种疾病的大脑中的无数区域的生物能分子。我们以前报道过异常高水平的 精神分裂症患者的乳酸水平与认知功能差密切相关。这 发现补充了我们的诱导多能干细胞（iPSC）和尸检工作显示更高的乳酸盐 受试者中iPSC衍生的皮层神经元和死后前扣带皮层中精神分裂症的水平 精神分裂症基于这一证据，我们假设， 精神分裂症是由于边缘回路中的生物能代谢受损， 精神分裂症中乳酸的产生或利用。具体地说，我们认为， 和从星形胶质细胞释放乳酸，再加上增加的摄取和利用乳酸，代替 葡萄糖摄取和氧化磷酸化，产生ATP，支持边缘系统神经元的可塑性。 电路.这个新的R 01项目使用互补但不同的方法来检查 精神分裂症的生物能量功能对于SA 1，我们将使用磁共振波谱（MRS）来 量化乳酸水平，并使用神经成像、临床、认知、 功能和代谢评估对于目标2，培养的源自iPSC的人神经元/星形胶质细胞 在SA 1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/功能的影响 在培养的人iPSC衍生的神经元/星形胶质细胞中的分子和细胞水平。在目标3中，我们将使用 生物信息学方法识别乳酸盐相关靶点，用于细胞亚型特异性研究 死后大脑中的生化/乳酸变化。综合起来，我们的目标将全面评估 临床、组织培养和尸检中乳酸盐和乳酸盐相关途径的扰动 精神分裂症的底物通过发展一个更复杂的理解的病理生理学， 精神分裂症，该项目将有助于确定生物能量途径的治疗目标 对这种使人衰弱的疾病进行干预。