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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: UG3TR003148
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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SUMMARY This supplemental application is to facilitate fulfillment of previously modified milestones prior to transition to the UH3 phase. This request for supplemental funds is a result of significant impediments to progress resulting from restriction of operational capacity during the COVID-19 pandemic. While significant progress has been made, the additional time required to complete the milestones will result in us incurring additional personnel and supply costs. The overall significance and scope of the project remains the same as the original proposal. 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 human cells, that recapitulate features of the neurobiology underlying the addictive process. The model we are developing focuses on a key component of addictive circuitry – the dopaminergic and GABAergic neurons of the midbrain, long recognized as responsible for mediating the reinforcing properties of many classes of abused drugs, including opioids. We are developing a multi-organ microphysiological system (MPS) based on human induced pluripotent stem cell (iPSC)-derived midbrain dopamine (DA)/Gamma-Amino Butyric Acid (GABA) neurons on a 3-dimensional platform that ultimately will incorporate microglia, blood-brain-barrier 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. Throughput will be increased by the integration of online sensors into the MPS for online detection of DA.


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: 2025 ( Subtotal = -$1,032 )
2025	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	National Center for Advancing Translational Sciences	000	1	10/1/2024	SUPPLEMENT FOR EXPANSION	-$1,032
														Subtotal = -$1,032

Issue Date FY: 2023 ( Subtotal = -$32,394 )
2023	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	National Center for Advancing Translational Sciences	000	1	5/15/2023	SUPPLEMENT FOR EXPANSION	-$32,394
														Subtotal = -$32,394

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	National Center for Advancing Translational Sciences	001	1	1/25/2022	SUPPLEMENT FOR EXPANSION	$0
2022	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	National Center for Advancing Translational Sciences	000	1	1/25/2022	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $531,057 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	National Center for Advancing Translational Sciences	002	1	9/15/2021	SUPPLEMENT FOR EXPANSION	$531,057
2021	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	National Center for Advancing Translational Sciences	001	1	9/13/2021	NEW	$0
2021	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	National Center for Advancing Translational Sciences	000	1	1/15/2021	NEW	$0
														Subtotal = $531,057

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	National Center for Advancing Translational Sciences	001	1	3/16/2020	NEW	$0
2020	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	National Center for Advancing Translational Sciences	000	1	3/12/2020	NEW	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $1,603,492 )
2019	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	National Center for Advancing Translational Sciences	000	1	9/26/2019	NEW	$1,603,492
														Subtotal = $1,603,492

Grand Total All Awards = $2,101,123

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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: UG3TR003148

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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