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Ubiquitin-system manipulations to probe and mitigate ethanol damage in neurons

Award Number: R21AA028106
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: 02/25/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2024

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Ubiquitin-system manipulations to probe and mitigate ethanol damage in neurons - PROJECT SUMMARY/ABSTRACT The consequences of prenatal alcohol exposure for the immature central nervous system represents a devastating but likely underestimated public health hazard, producing a range of ethanol-induced developmental defects including cognitive impairments having long-term impacts on society. Damage to neurons also includes cells within the retina, producing visual system facets of these fetal alcohol spectrum disorders (FASD). Critical gaps in knowledge remain regarding the specific mechanisms underlying ethanol- mediated damage to neurons, and their intrinsic vulnerabilities and neuroprotective features, which might be monitored, enhanced and/or exploited in some way to rescue neurons from damage. One proposed cellular target for ethanol damage is disruption in neurons of critical protein homeostasis pathways including the ubiquitin system. Our long-term goal is develop an understanding of the molecules and mechanisms producing photoreceptor neuron dysfunction and degeneration, and to elucidate potential rescue strategies. The overall objective of the current proposal is to determine the contribution of ubiquitin-system impairment to tissue damage by ethanol in these specific neurons, and the feasibility of ubiquitin-system manipulations to rescue neuronal function. The central hypothesis of our proposal is that binge-like ethanol exposure disrupts fundamental protein turnover mechanisms in photoreceptor neurons, undermining normal cell proteostasis. Our hypothesis is based on preliminary data from our lab demonstrating that binge-like exposure to ethanol produces loss of visual function in larval zebrafish, an advantageous model for FASD, with partial rescue of function via pharmacological enhancement of autophagy and the ubiquitin-proteasome system; ubiquitin-system impairment in photoreceptor-derived cells and photoreceptor neurons after ethanol exposure; and previously reported evidence for ubiquitin-system changes in the brain with ethanol. We plan to test our central hypothesis and accomplish the main objective of this proposal by completing the following specific aims: (1) determine the effects on ubiquitin-system manipulations on cone photoreceptor neuron function and proteostasis in the context of damaging exposure to alcohol; and (2) interrogate the changing landscape of ubiquitin-modified proteins in cone photoreceptors following ethanol exposure. These studies will involve molecular manipulations, including cell-specific expression of reporter proteins for ubiquitin- system impairment and CRISPR/Cas9 gene disruption specifically in cone photoreceptors; biochemistry; visual performance assays; ERG recordings; and photoreceptor-specific ubiquitin proteomics. The expected outcomes of these studies are an enhanced understanding of the relationship between early alcohol exposure, neuronal damage, and the ubiquitin system, and a mechanistic foundation for the possible development of therapeutic approaches to mitigate neuronal damage caused by alcohol abuse.


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: 2024 ( Subtotal = -$6,837 )
2024	2022	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Alcohol Research Programs	000	2	6/4/2024	NON-COMPETING CONTINUATION	-$6,837
														Subtotal = -$6,837

Issue Date FY: 2022 ( Subtotal = $216,874 )
2022	2022	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Alcohol Research Programs	001	2	6/22/2022	NON-COMPETING CONTINUATION	$21,688
2022	2022	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Alcohol Research Programs	000	2	2/1/2022	NON-COMPETING CONTINUATION	$195,186
														Subtotal = $216,874

Issue Date FY: 2021 ( Subtotal = $178,767 )
2021	2021	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Alcohol Research Programs	000	1	2/22/2021	NEW	$178,767
														Subtotal = $178,767

Grand Total All Awards = $388,804

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Ubiquitin-system manipulations to probe and mitigate ethanol damage in neurons

Award Number: R21AA028106

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: 02/25/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2024

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