Thursday, November 21, 2024 11/21/2024

A reduced Complexity Cross in BALB/c substrains to identify the genetic basis of oxycodone dependence phenotypes

Award Number: U01DA050243
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Substance use disorders (SUDs) are heritable psychiatric disorders with a significant genetic component. Opioid dependence, one of the most heritable SUDS, has reached epidemic proportions in the United States. Human genome-wide association studies (GWAS) are statistically underpowered to detect the majority of common genetic variation that contributes to opioid dependence. Discovery-based genetics in mammalian model organisms is a powerful complement to human GWAS and can uncover novel genetic factors, biological pathways, and gene networks underlying addiction traits. Mouse models are advantageous because they enable collection of the relevant brain tissue at the appropriate time points under controlled opioid dosing. Furthermore, gene editing permits the validation of functional variants in vivo within the same species on a controlled, genetic background. Reduced Complexity Crosses (RCCs) are genetic crosses between inbred mouse substrains that are nearly genetically identical and can vastly improve the speed at which causal genetic factors can be identified. Our primary objective is to use an RCC between BALB/c substrains to discover the genetic and molecular basis of opioid addiction-relevant traits at two stages of opioid dependence following repeated administration of the mu opioid receptor agonist oxycodone (OXY; the active ingredient of Oxycontin®). We found robust differences between BALB/c substrains in opioid adaptive behaviors, including state-dependent learning of OXY-induced locomotor stimulation and reward following limited, low-dose administration (1.25 mg/kg, IP) as well as the emotional-affective component of opioid withdrawal and weight loss following repeated high-dose administration (40 mg/kg, IP). In Aim 1, we will map quantitative trait loci (QTLs) underlying these OXY phenotypes in an RCC F2 cross. In Aim 2, we will map QTLs controlling gene expression (eQTLs) in the relevant brain tissues of control F2 mice and in OXY-trained F2 mice. We will then nominate candidate causal genes and nucleotides underlying behavior by integrating eQTL with behavioral QTL analysis. To increase precision in assigning candidate variants with the regulation of gene expression and behavior and to identify biological pathways and opioid-adaptive gene networks in specific cell types, we will use single nucleus RNA- seq (snRNA-seq) of brain tissue following limited, low-dose OXY and repeated high-dose OXY. In Aim 3, we will validate candidate functional variants underlying OXY phenotypes using CRISPR/Cas9 gene editing of each of the two alternate alleles onto each reciprocal substrain background. This approach will allow us to demonstrate both necessity and sufficiency of the quantitative trait nucleotides. The proposed studies will identify the genetic basis of unique opioid phenotypes across two stages of opioid dependence. Independent from gene discovery, these studies have broader application in revealing novel, actionable insight toward cellular adaptations at progressive stages of the opioid addiction process and potentially improving behavioral outcomes.


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 = $0 )
2025	2023	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Drug Use and Addiction Research Programs	002	5	11/7/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$787,856
2025	2023	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Drug Use and Addiction Research Programs	001	4	11/7/2024	NON-COMPETING CONTINUATION	-$709,989
2025	2022	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	3	11/7/2024	NON-COMPETING CONTINUATION	-$77,867
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $587,914 )
2024	2023	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Drug Use and Addiction Research Programs	001	4	7/24/2024	NON-COMPETING CONTINUATION	$0
2024	2023	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	4	12/12/2023	NON-COMPETING CONTINUATION	$0
2024	2023	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Drug Use and Addiction Research Programs	002	5	7/24/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$587,914
														Subtotal = $587,914

Issue Date FY: 2023 ( Subtotal = $709,989 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	4	6/30/2023	NON-COMPETING CONTINUATION	$709,989
														Subtotal = $709,989

Issue Date FY: 2022 ( Subtotal = $714,936 )
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	3	7/29/2022	NON-COMPETING CONTINUATION	$714,936
														Subtotal = $714,936

Issue Date FY: 2021 ( Subtotal = $647,133 )
2021	2021	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Drug Abuse and Addiction Research Programs	000	2	6/24/2021	NON-COMPETING CONTINUATION	$647,133
														Subtotal = $647,133

Issue Date FY: 2020 ( Subtotal = $602,148 )
2020	2020	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Drug Abuse and Addiction Research Programs	000	1	8/7/2020	NEW	$602,148
														Subtotal = $602,148

Grand Total All Awards = $3,262,120

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A reduced Complexity Cross in BALB/c substrains to identify the genetic basis of oxycodone dependence phenotypes

Award Number: U01DA050243

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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