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

基本信息

批准号：
10294239
负责人：
Christopher Marano
金额：
$ 72.18万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
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/10294239
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

项目摘要

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.

项目概要精神分裂症是一种无法治愈的毁灭性疾病，影响着全世界约 1% 的人口，造成了巨大的经济损失每年数十亿美元。该提议的科学前提是基于积累的成像，尸检、动物模型、遗传和生物信息学数据集中在生产变化上这种疾病中无数脑区的生物能分子。我们之前报告过异常高水平的活着的精神分裂症患者体内的乳酸与认知功能较差密切相关。这这一发现补充了我们的诱导多能干细胞 (iPSC)，尸检工作显示乳酸含量更高受试者 iPSC 衍生的皮质神经元和死后前扣带皮层中精神分裂症的水平患有精神分裂症。基于这一证据，我们假设认知功能减弱精神分裂症是由于边缘回路的生物能量代谢受损，病理性代谢增加所致。精神分裂症中乳酸的产生或利用。具体来说，我们假设产量增加星形胶质细胞释放乳酸，加上乳酸的吸收和利用增加，代替葡萄糖摄取和氧化磷酸化，产生 ATP 支持边缘系统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) 来使用神经影像学、临床、认知、功能和代谢评估。对于目标 2，培养源自 iPSC 的人类神经元/星形胶质细胞 SA1 中获得的用于评估乳酸生产和利用挑战的数据。我们将进一步明确功能乳酸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 衍生神经元/星形胶质细胞的分子和细胞水平。在目标 3 中，我们将使用生物信息学方法识别乳酸相关靶点，用于细胞亚型特异性研究死后大脑中的生化/乳酸变化。总而言之，我们的目标将全面评估临床、组织培养和尸检中乳酸和乳酸相关途径的扰动精神分裂症的底物。通过对病理生理学有更深入的了解精神分裂症，该项目将有助于确定生物能途径中的目标，以开发治疗方法对这种使人衰弱的疾病进行干预。