The Psychiatric Cell Map Initiative: Connecting Genomics, Subcellular Networks, and Higher Order Phenotypes

总结 全球精神疾病的负担，包括自闭症谱系障碍（ASD），智力残疾，癫痫， 图雷特精神分裂症和双相情感障碍，是巨大的，无论是在医疗保健衡量 支出、生产力损失或个人痛苦。不幸的是，人们对这一问题缺乏深刻的认识。 这些综合征的潜在分子生物学。然而，基因发现的最新进展正在设定 对这些精神疾病的理解的转变阶段。 了解病理生物学和开发新的治疗方法越来越依赖于 了解多种类型的生物网络，包括蛋白质之间的物理相互作用， 基因间的合成、非致死和上位相互作用。在这里，我们寻求支持的一个新的努力，精神病学 Cell Map Initiative（PCMI，www.pcmi.ucsf.edu），旨在全面了解这些复杂的 精神疾病的相互作用以及它们在患病和健康状态之间的差异。虽然我们将 这项工作将建立一个范式，以调查其他精神疾病， 未来的工作。PCMI是加州大学的一个多校区倡议，涉及加州大学旧金山分校弗朗西斯科， 加州大学圣地亚哥分校和加州大学伯克利分校，利用基因组学，蛋白质组学，高通量测序， 由多个PCMI开发的高级网络映射、计算分析和研究平台 调查人员在过去的十年里。因此，这些平台将被调整，以有效地产生， 在相关细胞类型中组装和分析与ASD相关的分子网络，以研究 和基于网络的个性化治疗。具体而言，在未来五年内，PCMI将寻求催化 ASD研究和治疗中的主要阶段转变，通过（1）全面绘制 与ASD相关的蛋白质之间的物理相互作用，揭示了蛋白质复合物和更高的生物学顺序。 人类大脑多种细胞类型中ASD的分子单位（2）绘制ASD的平行网络 使用基于CRISPR的方法在ASD基因之间合成非致死性和上位性相互作用（3） 建立强大的计算方法，最终用户软件和数据库，用于组装和使用 基础和临床模式下的ASD细胞网络图（4）将分子见解转化为 了解更高级的表型（5）建立一个关键质量的领先的研究人员集中在 （6）培训全球精神疾病患者，将PCMI扩展为全球协调伙伴关系 网络生物学及其应用研究的当前和下一代科学家专注于 精神疾病

SUMMARY The global burden of mental illness, including autism spectrum disorders (ASD), intellectual disability, epilepsy, Tourette disorder, schizophrenia and bipolar disorder, is enormous, whether measured in health care expenditures, lost productivity, or personal suffering. Unfortunately, there is a striking lack of insight into the underlying molecular biology of these syndromes. However, recent advances in gene discovery are setting the stage for a transformation in the understanding of these psychiatric disorders. Understanding pathobiology and developing novel treatments is becoming increasingly dependent on knowledge of biological networks of multiple types, including physical interactions among proteins and synthetic­lethal and epistatic interactions among genes. Here we seek support for a new effort, the Psychiatric Cell Map Initiative (PCMI, www.pcmi.ucsf.edu), aimed at comprehensively understanding these complex interactions in psychiatric disorders and how they differ between diseased and healthy states. While we will focus on ASD in this proposal, this work will establish a paradigm to investigate other psychiatric disorders in future work. The PCMI is a multi­campus initiative of the University of California, involving UC San Francisco, UC San Diego and UC Berkeley, which leverages genomics, proteomics, high­throughput sequencing, advanced network mapping, computational analysis, and research platforms developed by multiple PCMI investigators over the past decade. Thus primed, these platforms will be tuned to efficiently generate, assemble, and analyze molecular networks linked to ASD, in relevant cell types, with a view towards pathway and network­based personalized therapy. Specifically, over the next five years the PCMI will seek to catalyze major phase transitions in ASD research and therapy by (1) Comprehensively mapping the networks of physical interactions among proteins linked to ASD, revealing the protein complexes and higher­order molecular units underlying ASD in multiple cell types of the human brain; (2) Mapping the parallel networks of synthetic­lethal and epistatic interactions among ASD genes using CRISPR­based approaches; (3) Establishing the robust computational methodology, end­user software, and databases for assembly and use of ASD cell network maps in both basic and clinical modalities; (4) Translating molecular insights into an understanding of higher order phenotypes; (5) Building a critical mass of leading investigators focused on psychiatric disorders worldwide to expand PCMI into a global coordinated partnership; and (6) Training the current and next­generation of scientists in Network Biology and its applications to research focused on psychiatric disorders.