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

精神病学细胞图谱计划：连接基因组学、亚细胞网络和高阶表型

基本信息

批准号：
10447106
负责人：
Martin Kampmann
金额：
$ 370.18万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-05 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10447106
关键词：
ASCL1 gene Address Architecture Biological Biological Models Biology Bipolar Disorder Brain CRISPR interference CRISPR/Cas technology California Cataloging Cell model Cells Chemicals Clinical Clustered Regularly Interspaced Short Palindromic Repeats Complex Computer Analysis Computer software Computing Methodologies Coupled Cryoelectron Microscopy DNA sequencing DNA-Protein Interaction Data Databases Development Disease Docking Engineering Epilepsy Eukaryotic Cell Future Gene Combinations Gene Proteins Genes Genetic Genetic Screening Genomics Genotype Gilles de la Tourette syndrome Goals Health Expenditures High-Throughput Nucleotide Sequencing Human In Vitro Individual Intellectual functioning disability Knowledge Libraries Ligands Link Machine Learning Maps Mass Spectrum Analysis Measures Mental disorders Methodology Microscopy Modality Modeling Molecular Molecular Biology Mutation Network-based Neurobiology Neurons Ontology Organism Pathway interactions Patients Phase Transition Phenotype Point Mutation Productivity Proteins Proteomics Research Research Personnel Resolution Resources San Francisco Schizophrenia Scientist Slice Structure Syndrome Tadpoles Technology Therapeutic Therapeutic Intervention Tissues Training Translating Universities Variant Work Xenopus autism spectrum disorder automated image analysis base behavioral phenotyping cell type deep neural network excitatory neuron experimental study gene discovery gene network in vivo induced pluripotent stem cell inhibitory neuron insight interest link protein molecular phenotype multidisciplinary neural network neuropsychiatric disorder next generation novel personalized medicine precision medicine protein complex protein structure rare variant single-cell RNA sequencing small molecule success transcriptome

项目摘要

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.

概括全球精神疾病负担，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，都是巨大的不幸的是，人们对这些问题缺乏深入的了解。然而，基因发现的最新进展正在确定这些综合征的分子生物学。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中的相互作用以及它们在患病状态和健康状态之间的差异。该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 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经过过去十年的研究，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，以寻找途径具体来说，PCMI 将在未来五年内寻求推动。 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 的方法合成 ASD 基因之间的致死性和上位性相互作用；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 ASD 细胞网络图谱在基础和临床模式中的应用；(4) 将分子见解转化为 (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 扩大为全球协调伙伴关系；以及 (6) 培训网络生物学及其在研究中的应用的当前和下一代科学家的重点是精神疾病。