Functional Genomics of Human Brain Development

描述(由申请人提供)：了解生物系统的发展和功能组织所涉及的分子过程，以及它们在疾病状态中的变化，需要精确测量不同细胞类型和发育时间点上细胞机械的核酸和蛋白质水平的特性。由于人脑细胞的复杂性和无法进行实验，这一点在人脑中尤其难以实现。在这里，我们建议成立一个由多学科研究人员组成的中心，该中心将以独特和创新的方式在几种尖端基因组学方法的基础上发展，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中的人类和非人类灵长类(NHP；黑猩猩和猕猴)大脑的单细胞和组织产生的综合多维基因组规模数据来实现。我们还将使用这些新的信息来源来帮助识别自闭症谱系障碍(ASD)中的调节突变，以及阐明在自闭症谱系障碍中受损的常见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的背景下对人类特有的和ASD相关的调控突变进行建模和功能表征的方法。我们建议的中心将这些研究工作与广泛的人类基因组学和比较基因组学培训机会结合在一起。这种组织结构结合了每个关键调查员的专业知识，并建立了一个CEGS，其能力远远超过每个单独工作的个人，其资源将创造远远超过其各部分之和的能力。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，并为重大疾病的新的和更有效的治疗提供一条明确的途径。

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.