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

摘要 全球精神疾病负担，包括自闭症谱系障碍 (ASD)、智力障碍、癫痫、 抽动秽语症、精神分裂症和双相情感障碍，无论是在医疗保健中衡量，都是巨大的 支出、生产力损失或个人痛苦。不幸的是，人们对这个问题严重缺乏洞察力。 这些综合征的基础分子生物学。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发生转变的阶段。 了解病理生物学和开发新的治疗方法越来越依赖于 多种类型的生物网络的知识，包括蛋白质和蛋白质之间的物理相互作用 基因之间的合成致死和上位相互作用。在这里，我们寻求对一项新努力的支持，即精神病学 细胞图谱计划（PCMI，www.pcmi.ucsf.edu），旨在全面了解这些复杂的 精神疾病之间的相互作用以及它们在患病状态和健康状态之间的差异。虽然我们会 这项提案的重点是自闭症谱系障碍（ASD），这项工作将建立一个范式来研究其他精神疾病 未来的工作。 PCMI 是加州大学的一项多校区倡议，涉及加州大学旧金山分校、 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 开发的先进网络映射、计算分析和研究平台 过去十年的调查人员。因此，这些平台将被调整为有效地生成、 组装并分析相关细胞类型中与 ASD 相关的分子网络，以寻找途径 以及基于网络的个性化治疗。具体来说，在未来五年内，PCMI 将寻求促进 ASD 研究和治疗的主要阶段转变： (1) 全面绘制自闭症谱系障碍 (ASD) 研究和治疗的网络 与 ASD 相关的蛋白质之间的物理相互作用，揭示了蛋白质复合物和高阶 人脑多种细胞类型中 ASD 的分子单元；(2) 绘制 ASD 的并行网络 使用基于 CRISPR 的方法，ASD 基因之间的合成致死和上位相互作用；(3) 建立强大的计算方法、最终用户软件和数据库以进行组装和使用 基本和临床模式的 ASD 细胞网络图谱；(4) 将分子见解转化为 对高阶表型的理解；(5) 建立一批关键的主要研究人员，重点关注 世界范围内的精神疾病，将 PCMI 扩展为全球协调伙伴关系；(6) 培训 当前和下一代网络生物学科学家及其在研究中的应用重点 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.