Integrative Omics Center for Accelerating Neurobiological Understanding of Opioid Addiction (ICAN)

加速对阿片类药物成瘾的神经生物学理解的综合组学中心 (ICAN)

• 批准号: 10493702
• 负责人: Eric Otto Johnson
• 金额: $ 225.97万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10493702
• 关键词: Address; Alcohol Phenotype; Amygdaloid structure; Animal Model; Artificial Intelligence; Autopsy; Biological; Brain; Brain imaging; Brain region; Cells; Cessation of life; Choking; Clinical; Collection; Complex; Data; Development; Disease; Electronic Health Record; Ensure; Equation; Fertilization; Gene Expression Regulation; Genes; Genetic Transcription; Genomics; Goals; Heterogeneity; High Performance Computing; Human; Individual; Infrastructure; Ingestion; Institutes; Institution; Laboratories; Link; Mentors; Meta-Analysis; Methods; Modeling; Neurobiology; Nicotine; Nucleus Accumbens; Opiate Addiction; Opioid; Pathway interactions; Persons; Phenotype; Prefrontal Cortex; Public Health; Quantitative Trait Loci; RNA; Reproducibility; Research; Research Personnel; Resources; Risk; Rodent; Rodent Model; Sample Size; Science; Signal Transduction; Standardization; Study models; Translating; Translations; United States; Universities; Validation; Variant; Visualization; addiction; analysis pipeline; brain tissue; cohort; data exchange; data modeling; design; experimental study; gene network; genome wide association study; genomic locus; human model; improved; individual variation; innovation; multiple omics; novel; opioid user; outreach; statistics; synergism; tool; transcriptome

PROJECT SUMMARY/ABSTRACT The overarching goal of the Integrative Omics Center for Accelerating Neurobiological Understanding of Opioid Addiction (ICAN) is to identify biologically actionable drivers of opioid addiction (OA). We will (1) conduct large-scale integrated multi-omics studies of OA in humans, (2) integrate rodent–human studies to identify genes and gene networks implicated in OA, and (3) build a publicly available national omics resource for studying OA. Our cohering principle is that by integrating multiple omics across human and animal model data we will discover robust drivers of individual variation that predispose opioid users to addiction. The omics revolution has delivered many discoveries of such individual variation for complex diseases, including for nicotine and alcohol phenotypes, but not for OA. We see five fundamental challenges to rapid progress: (1) limited sample sizes and unaccounted-for phenotypic heterogeneity in genome-wide association studies (GWAS) of OA; (2) very limited human brain studies of gene dysregulation by OA; (3) poor translation between human and animal model studies; (4) lack of concurrent integration of multiple omics; and (5) limited practical access to, and poor harmonization of, OA omics data. To overcome these challenges, ICAN harnesses four Projects and two Cores: Project 1: Electronic Health Record Phenotyping and Genomics of Opioid Addiction Project 2: Gene Regulation in the Opioid Dependent Human Brain Project 3: Multi-species Approach to Opioid Addiction Project 4: Multi-omics Gene Network Identification Cores: Administrative Core and Synergy Core Across these Projects and Cores, we will (1) conduct the largest GWAS to date (N>100,000 cases) leveraging Genomic Structural Equation Modeling; (2) examine differential gene regulation across key brain regions (prefrontal cortex, nucleus accumbens, amygdala) in the largest collection of OA informative postmortem brains to date (N=641); (3) integrate rodent and human studies using GeneWeaver.org, polygenic transcriptome risk scores, and variant functionalizing experiments; and (4) apply explainable artificial intelligence, gene network mapping, and multiple lines-of-evidence integration for gene network discovery. Each Project is rigorously designed to make novel contributions. However, by integrating the diversity of ICAN’s science through the cross-fertilization and coordinating efforts of the Cores, we will leverage the agnostic discovery power of omics and place it within the context of functional neurobiology to make field-changing breakthroughs and identify actionable targets for development of OA treatments.

项目摘要/摘要 综合法的总体目标是加速神经生物学理解 阿片类药物成瘾（ICAN）是为了识别阿片类药物成瘾（OA）的生物学作用驱动因素。我们将（1） 在人类中对OA进行大规模综合综合研究，（2）综合啮齿动物 - 人类研究 确定OA中实施的基因和基因网络，（3）建立公开可用的国家OMICS资源 用于研究OA。我们的一致原则是，通过整合人类和动物模型的多个OMIC 数据我们将发现易于使用阿片类药物用户成瘾的个体变异的强大驱动因素。 奥米奇革命（Omics Revolution）为复杂疾病的这种个人变异提供了许多发现， 包括尼古丁和酒精表型，但不适合OA。我们看到快速的五个基本挑战 进度：（1）在全基因组中，有限的样本量和未计算的表型异质性 OA的协会研究（GWAS）； （2）OA对基因失调的人脑研究非常有限； （3） 人类和动物模型研究之间的不良翻译； （4）缺乏多重倍数的并发集成 omics; （5）OA OMICS数据的实际访问量和协调不佳的实际访问量有限。 为了克服这些挑战，ICAN利用了四个项目和两个核心： 项目1：阿片类药物成瘾的电子健康记录表型和基因组学 项目2：阿片类药物依赖人脑中的基因调节 项目3：阿片类药物成瘾的多种物种方法 项目4：多摩斯基因网络识别 核心：行政核心和协同核心 在这些项目和核心中，我们（1）迄今为止最大的GWA（n> 100,000案例） 利用基因组结构方程建模； （2）检查跨关键大脑的差异基因调节 最大的OA收藏集中的区域（前额叶皮层，伏伏核，杏仁核） 迄今为止，事后大脑（n = 641）; （3）使用geneweaver.org进行的啮齿动物和人类研究， 多基因转录组风险评分和变体功能化实验； （4）应用可解释 人工智能，基因网络映射和基因网络的多个证据集成 发现。每个项目都是严格设计的，以做出新颖的贡献。但是，通过整合 ICAN科学的多样性通过核心的交叉利用和协调努力，我们将 利用omics的不可知论能力，并将其置于功能性神经生物学的背景下 改变现场的突破并确定可行的OA治疗发展目标。