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

Award Number: UH3TR003148
ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $825,978 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	National Center for Advancing Translational Sciences	001	3	8/10/2023	NON-COMPETING CONTINUATION	$793,584
2023	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	National Center for Advancing Translational Sciences	000	2	5/17/2023	EXTENSION WITH OR WITHOUT FUNDS	$32,394
														Subtotal = $825,978

Issue Date FY: 2022 ( Subtotal = $793,652 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	National Center for Advancing Translational Sciences	000	2	9/12/2022	EXTENSION WITH OR WITHOUT FUNDS	$793,652
														Subtotal = $793,652

Grand Total All Awards = $1,619,630

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

Award Number: UH3TR003148

ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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