High-throughput profiling of compound abuse liabilities and identification of addiction-related drug targets using an iPSC-enabled platform

项目摘要/摘要 美国阿片成瘾危机的规模清楚地表明，迫切需要取得突破来评估 复合滥用责任，并能够发现新的止痛剂，将滥用可能性降至最低。我们 假设与成瘾相关的生理学改变可以在共培养的HiPSC来源的神经元中建模 和星形胶质细胞，并通过基因表达变化和相关的表型读数来检测。 我们的建议解决了严重缺乏与生理相关的工具能够分析相关的 通过执行特定的目的来支持人类神经系统成瘾的分子变化 包括：(1)培养多色hipsc来源的神经细胞和星形胶质细胞。 血统特定的荧光记者；(2)执行基于表型的试点机器学习 预测性滥用倾向筛查；以及(3)表型分析和基因表达分析相结合 描述与化合物接触相关的分子和细胞变化。成功完成 我们的项目将带来两个重大进展：(1)评估滥用潜力的重要新技术框架 开发过程早期的候选疗法以及(2)创新、可扩展的体外分析平台 这使得发现靶点和相关的候选疗法来减轻成瘾表型成为可能。这些 创新将使凯恩生物科学公司启动药物发现计划，这将为社会带来重大的 通过帮助遏制美国阿片类药物危机的增长并降低死亡率和经济负担而受益 与这次国家紧急状态有关。

Project Summary/Abstract The scale of the US opioid addiction crisis clearly evidences the critical need for breakthroughs to assess compound abuse liabilities and to enable discovery of new analgesics with minimal abuse potential. We hypothesize that altered addiction-associated physiology can be modeled in co-cultured hiPSC-derived neuronal and astrocyte cells and detected by profiling gene expression alterations and associated phenotypic readouts. Our proposal addresses the significant lack of physiologically-relevant tools capable of profiling relevant molecular changes that underpin addiction in the human nervous system by executing Specific Aims that encompass: (1) generation of a panel of multicolor hiPSC-derived neuronal and astrocyte cells with stable lineage specific fluorescent reporters; (2) execution of a phenotype-based pilot machine learning-enabled predictive abuse liability screen; and (3) combination of phenotypic profiling and gene expression analysis to characterize the molecular and cellular changes associated with compound exposure. Successful completion of our project will deliver 2 significant advances: (1) an important new technical framework to assess abuse potential of candidate therapeutics early in the development process and (2) an innovative, scalable in vitro assay platform that enables discovery of targets and associated candidate therapeutics to mitigate addiction phenotypes. These innovations will position Cairn Biosciences to initiate drug discovery programs that will bring significant societal benefit by helping to stem the growth of the US opioid crisis and reduce the mortality rates and economic burden associated with this National Emergency.