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Cellular and genomic mechanisms of the impact of ethanol on human neural model

Award Number: R01AA023797
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/05/2016
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Cellular and genomic mechanisms of the impact of ethanol on human neural model - Abstract and summary Alcohol use disorders (AUD) are complex behaviors accompanied by substantial morbidity, mortality and societal expense. Both genetic and environmental factors contribute to AUD. Despite progress in the human genetics of AUD, especially the identification of genome-wide significant AUD genetic risk variants, the neural basis of AUD in humans is largely unknown. Over the past five years, we have provided compelling evidence that: 1) Human neuronal cells derived from induced pluripotent stem (iPS) cells can be used as a tractable model to study neuropsychiatric disorders including AUD; 2) Ethanol exposure results in an inflammasome response in human neurons; 3) Human neurons carrying OPRM1 A118G minor gene variants showed enhanced sensitivity to opioids and ethanol; 4) Ethanol causes gene expression changes in both human neurons and glial cells; and 5) Microglia-containing 3D neural cultures can be a powerful system to study neuroinflammatory microglia-neuronal interactions. These premises provide a foundation for further mechanistic studies of the genetic and molecular underpinnings of AUD in human iPS cell-derived neural models. We also identified key gaps of knowledge in utilizing human neurons as a model system to study AUD that need to be filled, particularly: 1) how ethanol affects neuro-glial interactions in a human neural context is not known; and 2) how ethanol affects neurogenesis in a 3D context is not known. Moreover, 3) because of the polygenic nature of AUD, the contribution of single gene to AUD risk is likely small and the phenotypical manifestation is strongly influenced by individual’s genetic makeup. To address these outstanding questions, we hypothesize that ethanol impairs neuronal function via affecting neuroglial interactions, which is influenced by individual polygenic risk backgrounds. We have selected 36 subjects of both sexes with either extremely high polygenic risk score (PRS, top 10%ile, n=18 AUD) or low PRS (bottom 10%ile, n=18, no AUD) to test this hypothesis. We will differentiate iPS cells derived from these subjects into both 2D and 3D (i.e. brain organoids) neuronal cells co-cultured with human astrocytes and human microglia. Upon exposure to ethanol, these neural cells are subjected to a combination of morphological, immunocytochemical, electrophysiological, live cell imaging and genomic analyses to unravel the mechanism(s) underlying the impact of ethanol, focusing on neuro-astro-microglial interactions. In a relatively large collection of human iPS cells (n=36 lines) derived from subjects with extreme AUD PRSs, we hope to unravel the convergent phenotype and gene-networks that are linked to extreme high or low AUD PRSs. The results will advance our mechanistic understanding of the pathogenic role of AUD risk gene variants and the influence of polygenic risk background in a human neural system.


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 = $502,870 )
2025	2025	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Alcohol Research Programs	000	9	4/28/2025	NON-COMPETING CONTINUATION	$502,870
														Subtotal = $502,870

Issue Date FY: 2024 ( Subtotal = $498,990 )
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Alcohol Research Programs	004	8	3/27/2024	NON-COMPETING CONTINUATION	$449,091
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Alcohol Research Programs	005	8	5/15/2024	NON-COMPETING CONTINUATION	$49,899
2024	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Alcohol Research Programs	003	7	12/19/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$57,880
2024	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Alcohol Research Programs	001	7	11/10/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2024	2022	RUTGERS, THE STATE UNIVERSITY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Alcohol Research Programs	002	6	12/19/2023	COMPETING CONTINUATION	-$57,880
2024	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Alcohol Research Programs	000	6	11/9/2023	COMPETING CONTINUATION	$0
														Subtotal = $498,990

Issue Date FY: 2023 ( Subtotal = $550,567 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Alcohol Research Programs	000	7	4/19/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$550,567
														Subtotal = $550,567

Issue Date FY: 2022 ( Subtotal = $561,319 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Alcohol Research Programs	002	6	6/15/2022	COMPETING CONTINUATION	$1,277
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Alcohol Research Programs	000	6	4/25/2022	COMPETING CONTINUATION	$561,319
2022	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Alcohol Research Programs	001	5	6/15/2022	NON-COMPETING CONTINUATION	-$1,277
														Subtotal = $561,319

Issue Date FY: 2020 ( Subtotal = $352,102 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Alcohol Research Programs	000	5	1/31/2020	NON-COMPETING CONTINUATION	$352,102
														Subtotal = $352,102

Issue Date FY: 2019 ( Subtotal = $352,102 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Alcohol Research Programs	000	4	1/15/2019	NON-COMPETING CONTINUATION	$352,102
														Subtotal = $352,102

Issue Date FY: 2018 ( Subtotal = $749,602 )
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Alcohol Research Programs	000	3	1/24/2018	NON-COMPETING CONTINUATION	$316,891
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Alcohol Research Programs	002	3	9/12/2018	SUPPLEMENT FOR EXPANSION	$397,500
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Alcohol Research Programs	001	3	5/23/2018	NON-COMPETING CONTINUATION	$35,211
														Subtotal = $749,602

Issue Date FY: 2017 ( Subtotal = $352,103 )
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Alcohol Research Programs	001	2	7/19/2017	NON-COMPETING CONTINUATION	$35,211
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Alcohol Research Programs	000	2	1/6/2017	NON-COMPETING CONTINUATION	$316,892
														Subtotal = $352,103

Issue Date FY: 2016 ( Subtotal = $346,857 )
2016	2016	Rutgers, The State Univ Biomedical & Health Sciences	65 Davidson Road	Piscataway	NJ	08854	MIDDLESEX	USA	Alcohol Research Programs	000	1	2/5/2016	NEW	$346,857
														Subtotal = $346,857

Grand Total All Awards = $4,266,512

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Cellular and genomic mechanisms of the impact of ethanol on human neural model

Award Number: R01AA023797

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/05/2016

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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