Translational assessment of brain bioenergetic function in schizophrenia

项目摘要 精神分裂症是一种无法治愈的毁灭性疾病，影响着全球约1%的人口，造成 每年数十亿美元。这一提议的科学前提是基于累积成像， 身体解剖、动物模型、遗传和生物信息学数据汇聚在一起，研究生产过程中的变化 在这种疾病中，无数大脑区域中的生物能量分子。我们之前曾报道过异常高水平的 存活的精神分裂症患者中的乳酸与认知功能低下密切相关。这 这一发现补充了我们的诱导多能干细胞(IPSC)和验尸工作显示的较高乳酸 精神分裂症患者IPSC来源的皮质神经元和死后前扣带回皮质中的水平 患有精神分裂症。根据这一证据，我们假设认知功能减退 精神分裂症是由于边缘环路生物能量代谢受损，并伴有病理改变。 精神分裂症患者乳酸的产生或利用。具体地说，我们假设产量增加了 和从星形胶质细胞释放乳酸，加上乳酸的吸收和利用增加，而不是 葡萄糖摄取和氧化磷酸化，以产生ATP，以支持边缘神经元的可塑性 电路。这个新的R01项目使用补充但不同的方法来检查 精神分裂症的生物能量功能。对于SA1，我们将使用磁共振波谱(MRS)来 使用神经成像、临床、认知、 功能和新陈代谢评估。对于目标2，培养的人类神经元/星形胶质细胞来源于IPSCs 在SA1中获得，以评估乳酸盐生产和利用的挑战。我们会进一步界定功能界别 乳酸的产生对细胞能量代谢和神经元发育/功能的影响 培养的人IPSC来源的神经元/星形胶质细胞的分子和细胞水平。在目标3中，我们将使用 细胞亚型特异性研究中确定乳酸相关靶点的生物信息学方法 死后脑内生化/乳酸的变化。总而言之，我们的目标将全面评估 乳酸和乳酸相关途径在临床、组织培养和尸检中的扰动 精神分裂症的底物。通过对心脏的病理生理学有更深入的了解 精神分裂症，这个项目将有助于确定生物能量途径中的靶点，以开发治疗方法 对这种令人衰弱的疾病的干预。

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.