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

摘要 精神疾病的全球负担，包括自闭症谱系障碍(ASD)、智力残疾、癫痫、 抽动障碍、精神分裂症和双相情感障碍，无论是在医疗保健方面衡量，都是巨大的 支出、生产力损失或个人痛苦。不幸的是，人们对此缺乏深入的了解。 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 转变对这些精神疾病的理解的阶段。 理解病理生物学和开发新的治疗方法变得越来越依赖于 多种生物网络的知识，包括蛋白质和蛋白质之间的物理相互作用 基因之间的合成致命性和上位性相互作用。在这里，我们为一项新的努力寻求支持，精神病学 细胞图倡议(PCMI，www.pcmi.ucsf.edu)，旨在全面了解这些复杂的 精神障碍中的相互作用以及它们在疾病和健康状态之间的区别。虽然我们会 在这项建议中，这项工作将建立一个研究其他精神障碍的范例 未来的工作。PCMI是加州大学旧金山分校参与的一项多校区倡议。 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 调查人员在过去十年中。因此，这些平台将被调整为高效地产生、 组装并分析相关细胞类型中与ASD相关的分子网络，以期找到途径 和基于网络的个性化治疗。具体地说，未来五年，PCMI将寻求催化 ASD研究和治疗的主要相变：(1)全面绘制ASD研究和治疗网络 与ASD相关的蛋白质之间的物理相互作用，揭示了蛋白质复合体和更高的顺序 人脑多种细胞类型的自闭症潜在的分子单位;(2)映射 用基于CRISPR的方法;研究自闭症基因间的合成致死和上位性相互作用(3) 建立可靠的计算方法、最终用户软件和数据库，以便组装和使用 基础和临床模式下的自闭症细胞网络图;(4)将分子洞察力转化为 对高阶表型;的理解(5)建立一批主要的研究人员，专注于 全球精神障碍协会将PCMI扩展为全球协调伙伴关系;和(6)培训 当代和下一代科学家在网络生物学及其应用方面的研究重点 精神障碍。

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.