Multi-organ-on-chip device for modeling opioid reinforcement and withdrawal, and the negative affective component of pain: a therapeutic screening tool.

用于模拟阿片类药物强化和戒断以及疼痛的负面情感成分的多器官芯片设备：一种治疗筛选工具。

• 批准号: 10326436
• 负责人: Nureddin Ashammakhi
• 金额: $ 79.37万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-26 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10326436
• 关键词: 3-Dimensional; Acute; Agonist; Analgesics; Anhedonia; Biological Availability; Biological Models; Blood - brain barrier anatomy; Brain; Brain-Derived Neurotrophic Factor; Butyric Acids; Cells; Characteristics; Chemicals; Chronic; Clinical; Coculture Techniques; Complement; Detection; Development; Devices; Disinhibition; Dopamine; Drug Addiction; Drug Screening; Engineering; Epidemic; Exposure to; Future; Gene Expression; Gene Expression Profile; Genomic Library; Genomics; Goals; Human; Inflammatory; Intervention; Investigation; Libraries; Liver; Measures; Mediating; Metabolism; Microglia; Midbrain structure; Modeling; Molecular; Morphine; Neurobiology; Neuronal Plasticity; Neurons; Neurotransmitters; Online Systems; Opioid; Opioid Receptor; Opioid agonist; Output; Pain; Pain management; Pharmaceutical Preparations; Phase; Phosphotransferases; Process; Property; Proto-Oncogene Proteins c-akt; Psychological reinforcement; Psychopathology; Public Health; Relapse; Resource Sharing; Risk Factors; Role; Route; Scientist; Screening procedure; Signal Pathway; Specificity; System; Testing; Therapeutic; Therapeutic Intervention; Translating; Withdrawal; abuse liability; addiction; base; chemical resource; chronic pain; craving; design; drug of abuse; extracellular; gamma-Aminobutyric Acid; induced pluripotent stem cell; induced pluripotent stem cell technology; innovation; insight; kappa opioid receptors; kinase inhibitor; liver metabolism; metabolomics; microphysiology system; mu opioid receptors; negative affect; neurotransmission; new therapeutic target; novel; novel strategies; novel therapeutics; opioid abuse; opioid exposure; opioid use disorder; opioid withdrawal; organ on a chip; pain-related disability; prescription opioid; prescription opioid misuse; prevent; response; scaffold; screening; sensor; transcriptome sequencing; transmission process; treatment response

Abstract The significance of the public health crisis presented by the epidemic in opioid abuse is abundantly clear. There is a desperate need to develop therapeutics for treatment of opioid use disorder (OUD), and also to develop pain treatments that are non-addictive. Both of these goals will be served by high-throughput models amenable to drug screening, based on the use of human cells, that recapitulate features of the neurobiology underlying the addictive process. The model we propose to develop focuses on a key component of addictive circuitry – the dopaminergic and Gamma-Amino Butyric Acid (GABA)ergic neurons of the midbrain, long recognized as responsible for mediating the reinforcing properties of many classes of abused drugs, including opioids. We will develop multi-organ, microphysiological systems (MPSs) based on the use of human induced pluripotent stem cell (iPSC)-derived midbrain-fated dopamine (DA)/ GABA neurons on a three-dimensional platform that incorporates microglia, blood-brain-barrier (BBB) and liver metabolism components. RNA sequencing (RNAseq) and metabolomics analyses will complement the primary DA release measure to identify novel mechanisms contributing to chronic opioid-induced plasticity in DA responsiveness thought to underlie 1) the anhedonia characteristic of opioid withdrawal; 2) the negative affective component of chronic pain states; 3) craving and relapse. The chronic pain-relevant aspect of the model will be realized by examination of aversive kappa-mediated opioid effects on DA transmission in addition to the commonly abused mu opioid receptor agonists, and by incorporation of inflammatory-mediating microglia into the model. The incorporation of BBB and liver metabolism modules into the MPS platform will permit screening of drugs in the UH3 phase of the project that accounts for different routes of abused opioid administration and the bioavailability of potential therapeutic drugs, increasing translatability. Throughput will be increased by the integration of online sensors into the MPS for online detection of DA and other key analytes identified in the UG3 phase of the project. For addiction-treatment screening we will use a curated set of 100 chemical genomics probes from our UCLA kinase inhibitor library. The focus on kinases is based on their well-described role in plasticity, and will cover activities along the BDNF signaling pathway, mTORC2, mTORC1, AKT and other targets along the BDNF axis. Our selection of compounds/targets in this context will also be informed by the RNAseq and metabolomics results from the UG3 phase and we will supplement other drugs if needed from UCLA’s Molecular Screening Shared Resource chemical genomics libraries, which is over 3k probes strong. Although not proposed here, it is also important to point out that the MoC device could also be used to test the abuse liability of novel antinociceptive agents identified by other screening tools. With an interdisciplinary team of scientists and engineers, this proposal will build upon recent advances in organ-on-a-chip and iPSC technologies to create innovative MPSs with high potential to have significant clinical impacts in the future.

抽象的 绝对明显地说，流行病在阿片类药物滥用方面引发的公共卫生危机的重要性。 迫切需要发展治疗阿片类药物使用障碍（OUD）的理论，也需要 开发非依恋的疼痛治疗。这两个目标都将由高通量模型实现 基于人类细胞的使用，可以对药物筛查，从而概括了神经生物学的特征 额外过程的基础。我们建议开发的模型重点关注添加剂的关键组成部分 电路 - 中脑的多巴胺能和γ-氨基丁酸（GABA）ERGIC神经元 被公认为负责调解许多滥用药物的加强特性，包括 阿片类药物。我们将根据人类诱导的使用 多能干细胞（IPSC）衍生的中脑2胺（DA）/ GABA神经元在三维 融合了小胶质细胞，血脑屏障（BBB）和肝脏代谢成分的平台。 RNA 测序（RNASEQ）和代谢组学分析将完成主要DA释放措施以识别 有助于慢性阿片类药物诱导的可塑性的新型机制，在DA的反应性中被认为是1的基础） 阿片类药物戒断的触状特征； 2）慢性疼痛状态的负面情感成分； 3）渴望和复发。模型的慢性疼痛方面将通过检查来实现 除了通常滥用的Mu Oopioid外 受体激动剂，并通过将炎症性的小胶质细胞掺入模型中。合并 BBB和肝脏代谢模块进入MPS平台将允许在UH3阶段筛选药物 该项目解释了不同的滥用阿片类药物管理途径和潜在的生物利用度 治疗药物，增加了可翻译性。在线传感器的集成将增加吞吐量 进入国会议员，以在线检测该项目的UG3阶段确定的DA和其他关键分析物。为了 成瘾治疗筛查我们将使用UCLA的一组精选的100个化学基因组问题 激酶抑制剂库。对激酶的重点是基于它们在可塑性中描述的作用，并将覆盖 沿BDNF信号通路，MTORC2，MTORC1，AKT和其他目标沿BDNF轴的活动。 在这种情况下，我们选择的化合物/靶标也将由RNASEQ和代谢组学告知 UG3阶段的结果，如果需要UCLA的分子筛选，我们将补充其他药物 共享资源化学基因组学库，超过3K探针。虽然在这里没有提出过 指出MOC设备也可以用来测试新颖的滥用责任也很重要 通过其他筛选工具确定的抗伤害感受剂。与科学家的跨学科团队和 工程师，该提案将基于最新的A-A-Chip和IPSC技术的进步来创建 未来具有重大临床影响潜力的高潜力的创新MPS。