Friday, September 19, 2025 9/19/2025

Ethanol-induced disruption of kinase signaling pathways in brain development

Award Number: R01AA029114
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: 09/19/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Ethanol-induced disruption of kinase signaling pathways in brain development - ABSTRACT Fetal Alcohol Syndrome (FAS) is one of the leading causes of intellectual disability in the United States. The CDC estimates that 0.2-1.5 per 1000 live births are children with FASD, a syndrome characterized by disrupted fetal brain development and postnatal intellectual disability (ID). Disrupted connectivity including altered dendritic structure, axonal pathfinding and white matter tracts are common findings in FAS and are thought to be major contributors to ID. However, the cellular and biological targets of alcohol are diverse and it is not clear whether there are common underlying molecular mechanisms producing these disruptions. Identification of common molecular mechanism(s) would enable a deeper understanding of this disorder, inform studies of genetic susceptibilities and provide molecular targets for neuroprotective strategies. This proposal pursues our finding that acute ethanol (EtOH) exposure disrupts Src kinase activity in embryonic cortical neurons. Src is a critical non-receptor tyrosine kinase that sits at central positions in multiple signaling pathways including the Reelin-Dab1 signaling pathway which controls brain layer formation and dendritogenesis. We found that acute EtOH exposure activates Src and induces phosphorylation of many proteins including Dab1, an essential adaptor protein in the Reelin-signaling pathway. Remarkably, this dramatic increase in phosphorylation is followed by a sustained dephosphorylation response in which the phosphorylation of Reelin effectors including Dab1, Src itself and the actin severing protein n-cofilin return to baseline levels, or below. During the extended dephosphorylation phase, the Reelin-signaling pathway can no longer be activated by in vitro application of its ligand, Reelin. In AIM 1 of this proposal, we will determine whether Reelin-Dab1 silencing occurs in vivo after maternal dosing with EtOH. We will then determine whether genetic deficiency in Src prevents the phosphorylation and dephosphorylation responses. Genetically establishing the critical kinase that initiates the EtOH response in vivo will be essential for future neuroprotective efforts. We and others have shown that Reelin-Dab1 signaling controls Golgi-deployment in the forming dendrite. In AIM 2 we will examine whether Src activation and inactivation disrupts Golgi location and function. Disrupted Golgi function would be expected to impact membrane addition, glycosylation, secretion and appropriate expression of many proteins, with potential long term negative consequences on neuritogenesis and neuronal function. In AIM 3 we will determine whether the EphA3 signaling pathway is similarly disrupted by Src dysregulation. EphA3 is a receptor tyrosine kinase that is required for axonal and white matter tract development. We identified the activation site of EphA3 as a target of EtOH-induced Src dysregulation raising the possibility that EphA3 activation and then silencing may contribute to FASD-related white matter disruptions. Collectively, these studies will determine the contribution of EtOH-dependent Src dysregulation to altered developmental signaling in pathways critical for brain development.


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 = $366,750 )
2025	2025	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Alcohol Research Programs	000	4	8/28/2025	NON-COMPETING CONTINUATION	$366,750
														Subtotal = $366,750

Issue Date FY: 2024 ( Subtotal = $366,750 )
2024	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Alcohol Research Programs	000	3	8/6/2024	NON-COMPETING CONTINUATION	$366,750
														Subtotal = $366,750

Issue Date FY: 2023 ( Subtotal = $366,750 )
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Alcohol Research Programs	000	2	8/18/2023	NON-COMPETING CONTINUATION	$366,750
														Subtotal = $366,750

Issue Date FY: 2022 ( Subtotal = $366,750 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Alcohol Research Programs	000	1	9/19/2022	NEW	$366,750
														Subtotal = $366,750

Grand Total All Awards = $1,467,000

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Ethanol-induced disruption of kinase signaling pathways in brain development

Award Number: R01AA029114

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: 09/19/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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