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: 10703349
• 负责人: Nureddin Ashammakhi
• 金额: $ 79.36万
• 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/10703349
• 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; Microglia; Midbrain structure; Modeling; Molecular; Morphine; Neurobiology; Neuronal Plasticity; Neurons; Neurotransmitters; Online Systems; Opioid; Opioid Receptor; Opioid agonist; Organ; 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; chemical resource; chronic pain; craving; design; drug of abuse; extracellular; fabrication; 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.

摘要

项目成果

Application of lung microphysiological systems to COVID-19 modeling and drug discovery: a review.

• DOI: 10.1007/s42242-021-00136-5
• 发表时间: 2021
• 期刊: Bio-design and manufacturing
• 影响因子: 7.9
• 作者: Sun AM;Hoffman T;Luu BQ;Ashammakhi N;Li S
• 通讯作者: Li S

The Cells and the Implant Interact With the Biological System Via the Internet and Cloud Computing as the New Mediator.

• DOI: 10.1097/scs.0000000000007534
• 发表时间: 2021-07-01
• 期刊: The Journal of craniofacial surgery
• 作者: Ashammakhi N;Unluturk BD;Kaarela O;Akyildiz IF
• 通讯作者: Akyildiz IF

Organ-On-A-Chip Models of the Blood-Brain Barrier: Recent Advances and Future Prospects.

• DOI: 10.1002/smll.202201401
• 发表时间: 2022-09
• 期刊: Small (Weinheim an der Bergstrasse, Germany)
• 作者: Kawakita S;Mandal K;Mou L;Mecwan MM;Zhu Y;Li S;Sharma S;Hernandez AL;Nguyen HT;Maity S;de Barros NR;Nakayama A;Bandaru P;Ahadian S;Kim HJ;Herculano RD;Holler E;Jucaud V;Dokmeci MR;Khademhosseini A
• 通讯作者: Khademhosseini A