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Genetics of oxycodone intake in a hybrid rat diversity panel.

Award Number: U01DA053672
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Genetics of oxycodone intake in a hybrid rat diversity panel. - The steady rise in prescription opioids such as oxycodone has led to widespread abuse and deaths in the US. importance of drug pharmacokinetics in determining abuse potential, we have designed an oral operant rat self-administration (SA) procedure to model the pattern of drug intake of most human users/abusers of oxycodone, who initiate using oral tablets. Although genetic variants play important roles in susceptibility to opioid addiction, very limited data are available regarding specific genes and sequence variants that predispose to opioid addiction, and under what conditions. Given the We propose to use an innovative hybrid rat diversity panel (HRDP), which consists of 91 diverse rat genomes, to identify genetic variants influencing operant oxycodone intake in rats. The HRDP is unique in that it: 1) contains a high level of genetic diversity similar to that of human populations; 2) provides a way to control oxycodone exposure and to systematically study gene-by-environment and gene-by-drug interactions; and 3) integrates multi-omics addictome data: from genetics to epigenomics to brain connectomes to treatments. We have three aims: Aim 1: We will analyze whole genome sequencing data to define virtually all sequence variants that underlie heritable variations. De novo assemblies will be conducted using linked-reads data for selected high impact strains. Hi-C data (Dovetail Genomics) will be generated to further improve the quality of these assemblies. We will also generate RNA-seq data for key brain regions to obtain mechanistic insights into oxycodone intake. Aim 2: Using the HRDP (both sexes), we will phenotype oral oxycodone SA with a unique behavioral model. Rats will also be tested for sensitivity to pain, social behaviors, and anxiety-like traits - all signs of oxycodone withdrawal. Critically, we estimated the heritability (h2) of oxycodone intake in the range of 0.3 – 0.4. When using n=6/sex, the effective h2 is ~0.8 —sufficient for high precision mapping. Aim 3: We will use systems genetics methods to map and integrate behavioral phenotypes with sequence and transcriptome data. Both forward (QTL) and reverse (PheWAS) genetic methods will be used. We use new linear mixed models to map and test candidate genes with key cofactors using the GeneNetwork2 platform. Finally, we evaluate the translational relevance of candidate genes and biomarkers by comparison to GWAS cohorts and longitudinal reports of addiction in humans. Technical and conceptual advances that underlie this application are: new genomic methods combined with highly diverse rat populations allow us to quickly define novel gene variants that modulate key phases of opiate addiction. It is highly likely that a subset of variants and molecular networks we define will provide key components of a predictive framework linking sequence differences to human opioid addiction and potential treatments. This project uses new systems genetics approaches, open source genomic data and software, and a new type of hybrid rodent mapping panel to precisely define causal linkages between DNA variation and voluntary oxycodone intake.


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 = $671,923 )
2025	2025	UNIVERSITY OF TENNESSEE	62 S DUNLAP ST	MEMPHIS	TN	38103	SHELBY	USA	Drug Use and Addiction Research Programs	001	5	4/8/2025	NON-COMPETING CONTINUATION	$67,192
2025	2025	UNIVERSITY OF TENNESSEE	62 S DUNLAP ST	MEMPHIS	TN	38103	SHELBY	USA	Drug Use and Addiction Research Programs	000	5	2/27/2025	NON-COMPETING CONTINUATION	$604,731
														Subtotal = $671,923

Issue Date FY: 2024 ( Subtotal = $680,347 )
2024	2024	UNIVERSITY OF TENNESSEE	62 S DUNLAP ST	MEMPHIS	TN	38103	SHELBY	USA	Drug Use and Addiction Research Programs	001	4	4/25/2024	NON-COMPETING CONTINUATION	$0
2024	2024	UNIVERSITY OF TENNESSEE	62 S DUNLAP ST	MEMPHIS	TN	38103	SHELBY	USA	Drug Use and Addiction Research Programs	002	4	4/30/2024	NON-COMPETING CONTINUATION	$68,033
2024	2024	UNIVERSITY OF TENNESSEE	62 S DUNLAP ST	MEMPHIS	TN	38103	SHELBY	USA	Drug Use and Addiction Research Programs	000	4	1/22/2024	NON-COMPETING CONTINUATION	$612,314
														Subtotal = $680,347

Issue Date FY: 2023 ( Subtotal = $680,347 )
2023	2023	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Drug Use and Addiction Research Programs	000	3	1/12/2023	NON-COMPETING CONTINUATION	$680,347
														Subtotal = $680,347

Issue Date FY: 2022 ( Subtotal = $683,997 )
2022	2022	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Drug Use and Addiction Research Programs	000	2	2/22/2022	NON-COMPETING CONTINUATION	$615,596
2022	2022	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Drug Use and Addiction Research Programs	002	2	9/30/2022	NON-COMPETING CONTINUATION	$0
2022	2022	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Drug Use and Addiction Research Programs	001	2	3/18/2022	NON-COMPETING CONTINUATION	$68,401
														Subtotal = $683,997

Issue Date FY: 2021 ( Subtotal = $676,136 )
2021	2021	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Drug Use and Addiction Research Programs	000	1	4/8/2021	NEW	$676,136
														Subtotal = $676,136

Grand Total All Awards = $3,392,750

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Genetics of oxycodone intake in a hybrid rat diversity panel.

Award Number: U01DA053672

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 04/15/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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