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Systems genetics of premorbid and cocaine use traits in a rat reduced complexity cross

Award Number: U01DA055299
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: 03/07/2024
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Systems genetics of premorbid and cocaine use traits in a rat reduced complexity cross - PROJECT SUMMARY Stimulant use disorders (e.g., cocaine, methamphetamine) are a major public health concern. Despite a heritability of ~40-50%, genome-wide association studies (GWAS) have identified very few loci, including one hit for cocaine (COC) dependence that maps to FAM53B, a gene also identified via expression quantitative trait locus (QTL) analysis to be associated with COC self-administration in mice. The primary objective is to rapidly identify novel genetic factors in rats that contribute to premorbid risk (compulsivity, impulsivity) and cocaine use traits in a spontaneously hypertensive rat (SHR) reduced complexity cross (RCC). A rodent systems genetics approach triangulates on discovery-based genetic and multi-level functional genomic analysis and can provide a more rapid genetic and neurobiological insight into drug action and neuroplasticity underlying addiction. For several years, the contact PI has been employing mouse reduced complexity crosses (RCCs) between near-isogenic inbred substrains to facilitate gene mapping, validation, and mechanisms. Because rodent substrains are > 99% genetically identical and contain several orders of magnitude fewer variants compared to classical inbred strains, mapping quantitative trait loci (QTLs) in RCCs yields orders of magnitude fewer causal candidate genes to consider. When combined with functional genomics, RCCs can rapidly lead to causal gene and variant identification. Our preliminary studies establish robust, heritable differences in premorbid impulsivity and compulsivity, sucrose reward sensitivity, and multiple COC use traits between SHR/NCrl and SHR/NHsd substrains, including COC-induced locomotor activity, COC IVSA taking, seeking, and intake cycles, demonstrating feasibility for gene mapping in an RCC. In Aims 1 and 2, we will pioneer the use of a rat RCC where we will conduct whole genome sequencing (WGS) and map behavioral QTLs and expression QTLs (eQTLs) from nucleus accumbens (NAC) and prefrontal cortex (PFC) at the whole transcript and exon levels in an F2 cross comprising COC-trained versus yoked saline (SAL)-trained rats. In Aim 3, we will conduct proteomic analysis of PFC and NAC from COC vs. yoked SAL-trained rats to triangulate on high confidence candidate quantitative trait genes (QTGs) and variants (QTVs) as we build functional connections between DNA variants, transcriptional regulation, protein translation, and cell signaling adaptations underlying premorbid and cocaine use traits. These studies pioneer the use of a rat RCC combined with deep behavioral phenotyping to rapidly identify high-confidence candidate novel genetic factors and molecular mechanisms influencing premorbid risk factors and cocaine use traits. Future gene editing of candidate causal gene variants will be modeled on the two near-isogenic SHR backgrounds to demonstrate necessity (mutation correction; “rescue”) and sufficiency (mutation induction). Deliverables include WGS’s of SHR substrains for future RCCs for complex trait analysis as well as adaptive rat transcriptomic and proteomic datasets in key brain regions of the mesocorticolimbic circuitry that can be further mined by investigators and hopefully inform therapeutics.


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 = $604,029 )
2025	2025	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Drug Use and Addiction Research Programs	002	4	2/28/2025	NON-COMPETING CONTINUATION	$543,626
2025	2025	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Drug Use and Addiction Research Programs	003	4	4/10/2025	NON-COMPETING CONTINUATION	$60,403
2025	2024	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Drug Use and Addiction Research Programs	001	3	11/7/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$307,097
2025	2023	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	2	11/7/2024	NON-COMPETING CONTINUATION	-$307,097
														Subtotal = $604,029

Issue Date FY: 2024 ( Subtotal = $721,312 )
2024	2024	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Drug Use and Addiction Research Programs	002	3	8/16/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$721,312
2024	2023	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Drug Use and Addiction Research Programs	001	2	8/15/2024	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	2	12/26/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $721,312

Issue Date FY: 2023 ( Subtotal = $706,305 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Drug Use and Addiction Research Programs	001	2	2/27/2023	NON-COMPETING CONTINUATION	$706,305
2023	2022	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	1	10/20/2022	NEW	$0
														Subtotal = $706,305

Issue Date FY: 2022 ( Subtotal = $737,859 )
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	1	4/15/2022	NEW	$737,859
														Subtotal = $737,859

Grand Total All Awards = $2,769,505

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Systems genetics of premorbid and cocaine use traits in a rat reduced complexity cross

Award Number: U01DA055299

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: 03/07/2024

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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