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

项目总结 22q11.2微缺失综合征(22q11.2DS)与精神病风险增加约20倍相关。 脑成像研究一直表明，大脑皮层的功能连接异常。 使用人类诱导多能干细胞(HiPSC)来源的大脑皮层神经元的临床前研究， 发现线粒体缺陷、神经元过度兴奋和钙信号缺陷，支持这一发现 大脑皮层回路功能障碍。然而，22q11.2的确切细胞和分子机制 缺失导致大脑皮层发育异常，大脑皮层功能有待阐明。 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，表明全球代谢发生了变化。尽管有越来越多的证据 对于22q11.2DS的线粒体和神经元功能障碍，代谢和线粒体的失调 在人类发育中的大脑皮层中的存在仍不清楚。 我们将检验这一假设，即人类线粒体缺陷始于增殖的神经前体细胞和 损害暂时性线粒体成熟，诱导代谢重新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的疾病模型中不那么明显。 目标1将在小鼠的HCS和前脑切片中识别皮质发育过程中的线粒体缺陷 22q11.2DS模型，使用先进的显微镜和功能分析。 AIM 2将评估HCS和前脑切片在皮质发育过程中的代谢变化 22q11.2DS小鼠模型，使用非靶向代谢组学和细胞类型特定的代谢谱。 目标3将确定代谢途径作为治疗干预的目标，通过测试 已知可增强线粒体功能的药物(如烟酰胺核苷、白藜芦醇、苯扎贝特)。 我们的多学科项目将确定最初的时间和确切的代谢和线粒体变化 在22q11.2DS中大脑皮层的发育过程中，精确定位药物发现的代谢途径， (Ii)评估物种间的差异，以及(Iii)建立体外人类神经代谢组学分析方法，以研究 其他因遗传或环境原因引起的代谢紊乱。

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.