Identification of metabolic alterations during cortical development in a human cellular model for 22q11.2 deletion syndrome

22q11.2 缺失综合征人类细胞模型皮质发育过程中代谢变化的鉴定

基本信息

批准号：
10552046
负责人：
Anca Mirabela Pasca
金额：
$ 77.3万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-18 至 2026-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10552046
关键词：
22q11.2 Action Potentials Animal Model Bezafibrate Biogenesis Biological Assay Blood specimen Brain Injuries Brain imaging Calcium Calcium Signaling Cell model Cells Cerebral cortex DNA Sequence Alteration Defect Development DiGeorge Syndrome Diagnosis Disease model Electron Microscopy Electrophysiology (science)Enhancers Etiology Functional disorder Generations Genes Genetic Diseases Genetic Transcription Genus Hippocampus Glycolysis Goals Human Image Impairment In Vitro Individual Light Lysine Metabolic Metabolic Diseases Metabolic Pathway Metabolism Microscopy Mitochondria Mitochondrial Diseases Molecular Morphology Movement Multiplexed Ion Beam Imaging Mus Neurodevelopmental Disorder Neurologic Deficit Neuronal Differentiation Neuronal Dysfunction Neurons Oxidative Phosphorylation Pharmaceutical Preparations Phenotype Predisposition Production Proliferating Prosencephalon Public Health Research Proposals Resistance Resveratrol Rodent Model Side Specificity Stress Tests Synapses Syndrome Technology Testing Therapeutic Intervention Time Tissue-Specific Gene Expression aerobic glycolysis brain repair cell type drug discovery experimental study fetal imaging study induced pluripotent stem cell insight metabolic profile metabolomics microdeletion mitochondrial dysfunction mouse model multidisciplinary nerve stem cell neuropsychiatric disorder nicotinamide-beta-riboside postmitotic preclinical study progenitor psychosis risk targeted treatment transcriptome sequencing

项目摘要

PROJECT SUMMARY The 22q11.2 microdeletion syndrome (22q11.2 DS), is associated with ~20-fold increased risk for psychosis. Brain imaging studies have consistently demonstrated abnormal functional connectivity in the cerebral cortex. Preclinical studies using cerebral cortex neurons derived from human induced pluripotent stem cells (hiPSC), revealed mitochondrial defects, neuronal hyperexcitability and calcium signaling defects, supporting the findings of cortical circuit dysfunction. However, the exact cellular and molecular mechanisms by which the 22q11.2 deletion leads to abnormal development and function of the cerebral cortex remain to be elucidated. The 22q11.2 chromosomal region contains 9 genes associated with mitochondrial energy production. Human blood samples revealed increased glycolysis, suggesting global metabolic alterations. Despite growing evidence for mitochondrial and neuronal dysfunction in 22q11.2 DS, the metabolic and mitochondrial dysregulations present in the human developing cerebral cortex remain unknown. We will test the hypothesis that human mitochondrial defects begin in proliferating neural progenitors and impair temporal mitochondrial maturation, induce metabolic reprogramming and subsequent neuronal function defects. We hypothesize these metabolic abnormalities are less pronounced in rodent models of disease. Aim 1 will identify mitochondrial defects during cortical development in hCS and forebrain sections from a mouse model for 22q11.2 DS, using advanced microscopy and functional assays. Aim 2 will assess for metabolic alterations during cortical development in hCS and forebrain sections from a mouse model for 22q11.2 DS, using untargeted metabolomics and cell type-specific metabolic profile. Aim 3 will identify metabolic pathways as targets for therapeutic interventions by testing the rescue potential of drugs known to enhance mitochondrial function (e.g. nicotinamide riboside, resveratrol, bezafibrate). Our multidisciplinary project will identify the initial timing and the exact metabolic and mitochondrial alteration during the development of the cerebral cortex in 22q11.2 DS and pinpoint metabolic pathways for drug discovery, (ii) assess for interspecies differences, and (iii) establish in vitro human neurometabolomics assays to study other metabolic disorders of genetic or environmental etiology.

项目摘要 22q11.2微骨骼综合征（22q11.2 ds）与精神病风险增加约20倍。脑成像研究一直表明大脑皮层的功能连通性异常。使用源自人类诱导多能干细胞（HIPSC）的脑皮质神经元的临床前研究，揭示了线粒体缺陷，神经元过度兴奋性和钙信号传导缺陷，支持了发现皮质电路功能障碍。但是，22q11.2的精确细胞和分子机制缺失导致脑皮质的异常发育和功能尚待阐明。 22q11.2染色体区域包含9个与线粒体能量产生相关的基因。人类血液样本显示糖酵解增加，表明全球代谢改变。尽管有越来越多的证据对于22q11.2 ds中的线粒体和神经元功能障碍，代谢和线粒体功能障碍存在于人类发展的大脑皮层中的人仍然未知。我们将检验以下假设，即人的线粒体缺陷始于增殖神经祖细胞和临时线粒体成熟损害，诱导代谢重编程和随后的神经元功能缺陷。我们假设这些代谢异常在啮齿动物模型中不太明显。 AIM 1将在HCS和前脑截面的皮质发育过程中识别线粒体缺陷使用高级显微镜和功能分析的22q11.2 ds的模型。 AIM 2将评估HCS和前脑部分皮质发育过程中的代谢改变。使用非靶向的代谢组学和细胞类型特异性代谢剖面的鼠标模型，用于22q11.2 ds。 AIM 3将通过测试的救援潜力来识别代谢途径作为治疗干预措施的靶标已知可以增强线粒体功能的药物（例如，烟酰胺核糖剂，白藜芦醇，bezafibrate）。我们的多学科项目将确定最初的时机以及确切的代谢和线粒体改变在22q11.2 ds的大脑皮层开发过程中，并确定了用于药物发现的代谢途径，（ii）评估种间差异，（iii）建立体外人类神经代谢组学测定法遗传或环境病因的其他代谢疾病。