Understanding Brain Development Through the Lens of Metabolism

从新陈代谢的角度理解大脑发育

• 批准号: 9915985
• 负责人: Aparna Bhaduri
• 金额: $ 10.21万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9915985
• 关键词: Adult; Age; Area; BRAIN initiative; Brain; Brain region; Cell Communication; Cell Differentiation process; Cell Maintenance; Cell Shape; Cells; Cerebral cortex; Collaborations; Communication; Communities; Complex; Data; Data Set; Development; Disease; Gene Expression; Genes; Genetic Transcription; Goals; Heterogeneity; Human; Human Development; In Vitro; Laboratories; Link; Lipids; Measures; Metabolic; Metabolic Marker; Metabolism; Modeling; Molecular; Morphology; Mus; Mutate; Neuraxis; Neurodevelopmental Disorder; Neurons; Neuropeptides; Pattern; Phase; Play; Population; Postdoctoral Fellow; Research; Resolution; Resources; Role; Sampling; Sensory; Signal Transduction; Specific qualifier value; Specificity; Structure; Surveys; Synapses; Technology; Testing; Therapeutic Intervention; Transcriptional Regulation; Work; brain circuitry; cell type; developmental disease; excitatory neuron; experience; experimental study; follow-up; genetic manipulation; human model; improved; insight; lens; lipid metabolism; lipid transport; multimodality; neurogenesis; new technology; prenatal; progenitor; programs; single cell sequencing; stem cell biology; stem cell fate; stem cell therapy; stem cells; transcription factor; transcriptome; transcriptomics

The human cerebral cortex is a complex structure comprised of distinct areas with specialized functions and connectivity patterns. Recent advances in single-cell sequencing have started to illuminate additional cell type diversity that exists in both mouse and human brains, with significant transcriptional areal differences between otherwise corresponding excitatory cell types. Understanding how these cell types emerge is essential to understanding how neurodevelopmental disorders may arise, as well as to better model human cortical cell types and to understand how stem cell therapies may best be developed in an area specific manner. Moreover, a number of transient populations of cell types exist solely during development and may hold crucial clues as to what signals determine areal identity in the human cortex. Preliminary data suggests that a small number of differences in progenitor cells cascade into larger differences in excitatory neurons. Moreover, initial characterizations of these area specific genes indicate an enrichment of lipid metabolism and transport genes. The lipidome is an aspect of the central nervous system that is highly evolved and complex in humans and comprises half of the central nervous system mass. Additionally, certain metabolites have been characterized to regulate stem cell maintenance and differentiation, and in a number of neurodevelopmental disorders are mutated or dysregulated. Lipids are known to be important for synaptic communication or neuropeptide signaling, but the role of lipids in defining cell type or progenitor fate is heretofore undescribed. Our preliminary data in human cortical development suggests there is incredible lipid diversity, as well as cell type and area specificity of certain classes of lipids. Thus, the specific aims of this project first seek to characterize the developing human cerebral cortex across multiple regions and ages using both transcriptomic and lipidomic approaches (K99 phase), while also optimizing technologies to generate a “Rosetta Stone” between lipid and transcriptional identity (K99 + R00 phase). Utilizing our preliminary data, a list of candidate transcription factors and lipid metabolism genes will be surveyed for a role in regulating areal identity. By genetically manipulating progenitor cells, we will assess the impact upon resultant area identity of neurons. Integrating these experiments will enable a hierarchical determination of how metabolism and transcriptional regulation cross-talk to determine cell fate decisions in cortical progenitors. Together, these descriptive datasets and mechanistic experiments will improve our understanding of cell types and their specification from progenitors in the human cortex, and offer additional insight into how developmental disorders may emerge and eventually how they may be targeted, potentially through a metabolic axis of therapeutic intervention. The unique datasets generated through this will serve as a resource for multimodal cell type analysis and follow up mechanistic study not only for our research group, but also for the community at large.

人体大脑皮层是一个复杂的结构，该结构完成了具有专业功能和连通性模式的不同区域。单细胞测序的最新进展已开始阐明小鼠和人大脑中存在的其他细胞类型多样性，在其他相应的兴奋性细胞类型之间存在显着的转录面差异。了解这些细胞类型紧急情况对于理解如何出现神经发育障碍以及更好地模拟人体皮层细胞类型以及了解如何最好以特定区域的方式开发干细胞疗法。此外，发育过程中存在许多细胞类型的瞬态群体，并且对于哪些信号决定人类皮质中的面积身份可能会持有关键群集。初步数据表明，祖细胞细胞中少数差异级联成兴奋性神经元的差异。此外，这些区域特定基因的初始特征表明脂质代谢和转运基因的富集。脂肪组是中枢神经系统的一个方面，在人类中已经高度发展且复杂，包括中枢神经系统质量的一半。此外，已经对某些代谢产物进行了表征来调节干细胞的维持和分化，并且在许多神经发育疾病中，突变或失调。已知脂质对于突触通信或神经肽信号传导很重要，但是脂肪在定义细胞类型或祖细胞命运中的作用却是未描述的。我们人类皮质发育中的初步数据表明，脂质的脂质多样性以及某些类别的脂质的细胞类型和面积特异性。这是该项目的具体目的首先试图使用转录组和脂肪组方法（K99阶段）来表征多个区域和年龄之间发展中的人脑皮质，同时还优化了技术以在脂质和转录身份之间产生“ Rosetta Stone”（K99 +​​ R00相）。利用我们的初步数据，将调查候选转录因子和脂质代谢基因的列表，以在调节中发挥作用。通过遗传操纵祖细胞，我们将评估对神经元所得面积身份的影响。整合这些实验将能够层次确定新陈代谢和转录调节如何确定皮质祖细胞脂肪的决策。总之，这些描述性数据集和机械实验将提高我们对人皮层中祖细胞类型的理解及其规格，并提供更多有关如何出现发育障碍的信息，并最终通过疗法干预的代谢轴进行靶向靶向。通过这将是多模式细胞类型分析的资源，不仅对我们的研究小组，而且对整个社区进行了机械研究。