Functional Genomics of Human Brain Development

描述（由申请人提供）：了解涉及生物系统发育和功能组织的分子过程，以及它们在疾病状态中的改变，需要精确测量不同细胞类型和发育时间点的细胞机制的核酸和蛋白质水平特性。由于人脑细胞的复杂性和实验的不可接近性，这在人脑中尤其难以实现。在这里，我们提议建立一个由多学科研究人员组成的研究中心，以独特和创新的方式开发几种尖端的基因组学方法，以阐明人类大脑发育和进化的分子网络。这将通过生成和探索从发育和成年人类和非人类灵长类动物（NHP；黑猩猩和猕猴）大脑的单细胞和组织中产生的综合多维基因组规模数据来实现。我们还将利用这些新的信息来源来促进自闭症谱系障碍（ASD）中调节突变的识别，以及阐明ASD中常见的和细胞类型特定的分子网络。最后，我们实现了在小鼠大脑发育背景下对人类特异性和asd相关的调控突变进行建模和功能表征的方法。我们提议的中心将这些研究工作与人类和比较基因组学方面的广泛培训机会结合起来。这种组织结构结合了每个关键研究人员的专业知识，并建立了一个CEGS，该CEGS的能力远远超过每个人单独工作的能力，其资源将创造的能力远远超过其各部分的总和。我们的工作将为重建人类发育和疾病状态的分子网络铺平道路，并为新的和更有效的主要疾病治疗提供明确的途径。

DESCRIPTION (provided by applicant): Understanding the molecular processes involved in the development and functional organization of biological systems, as well as their alterations in disease states, requires precise measurements of nucleic acid- and protein-level properties of cellular machinery across different cell types and developmental time points. This is particularly difficult to achieve in the human brain due to its cellular complexity and inaccessibility for experimentation. Here, we propose a Center with a multi-disciplinary group of investigators that will develop upon several cutting-edge genomics approaches in a unique and innovative way to elucidate molecular networks underlying human brain development and evolution. This will be achieved through the generation and exploration of integrated multi-dimensional genomic scale data generated from single cells and tissues of developing and adult human and non-human primate (NHP; chimpanzee and macaque) brains. We will also use these new sources of information to facilitate the identification of regulatory mutations in autism spectrum disorders (ASD) as well as to elucidate common and cell type specific molecular networks compromised in ASD. Finally, we implement approaches to model and functionally characterize of human-specific and ASD-associated regulatory mutations in the context of mouse brain development. Our proposed Center couples these research efforts with extensive training opportunities in human and comparative genomics. This organizational structure combines the expertise of each individual key investigator and establishes a CEGS that is capable of much more than each individual working alone and whose resources will create capabilities that are much more than the sum of its parts. Our work will pave the way for reconstructing molecular networks in human development and disease states, and provide a clear path to new and more effective treatments of major disorders.