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FASD Inhibition of ASPH-Notch Mediates Adolescent Cerebral White Matter Pathology-Potential Utility of Non-invasive Extracellular Vesicle Assays

Award Number: R01AA011431
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Long-term effects of fetal alcohol spectrum disorder (FASD) on the CNS vary with exposure dose, duration, and timing. Despite decades of research, we still lack efficient means of detecting and therapeutically targeting the damage. However, progress may have been limited by our failure to attend to the full spectrum of brain pathology linked to neurobehavioral dysfunction. For example, besides neurons, alcohol exposures across the lifespan, but especially during development, exert toxic/metabolic effects that impact the integrity of white matter (WM) myelin, axons, and oligodendrocytes (OLs), yet the mechanisms are poorly understood. Dysfunction or loss of OLs compromises the structure and function of myelin, impairing axonal conductivity. Preliminary studies showed that developmental exposures to ethanol reduce the expression of mature myelin-associated genes and proteins, in part due to impaired maturation of oligoprogenitor cells and/or survival of mature OLs. Attendant hypomyelination and dysmyelination render WM axons vulnerable to toxic/metabolic injury and degeneration with loss of synaptic connections. This competing renewal R37 application builds on our previous gains that mechanistically linked ethanol-impaired insulin and IGF-1 signaling through PI3K-Akt and downstream pathways to deficits in neuronal survival and migration during development. Another critical success of those experiments was that they revealed how ethanol inhibition of aspartyl-asparaginyl-ß-hydroxylase (ASPH) and Notch impair survival, maturation and migration of immature CNS neurons. However, empirical observations and subsequent preliminary studies led to the hypothesis that WM OLs may be similarly impaired by ethanol via disruption of Akt-mTOR-mTORC1/2 which alters the composition and integrity of WM myelin. We now propose to extend these gains by determining how ethanol inhibits insulin/IGF-Akt-mTOR-mTORC1/2 signaling and reduces ASPH-Notch activation in relation to WM structure and function during postnatal and adolescent development. Aim 1 will delineate mechanisms of long term FASD WM and OL pathologies by examining developmental stage-associated impairments in signaling through insulin/IGF-1-PI3K-Akt-mTOR-mTORC1/2, and ASPH-Notch activation. Aim 2 will assess FASD dose- dependent inhibition of sulfatide (ST) in relation to impairments in OL maturation; in many CNS diseases, ST depletion in WM mediates cognitive-motor deficits. Aim 3 stems from preliminary studies showing that ethanol’s effects on WM sphingolipid profiles, including STs, are detectable in peripheral blood circulating extracellular vesicles (EVs). Therefore, we propose to examine the utility of MALDI Mass Spectrometry (MS) EV assays for non-invasive detection of WM pathology and responses to treatments that restore ASPH-Notch pathways needed for OL/WM maturation and function. Our hypotheses will be addressed with in vivo, slice culture, and isolated OL models, quantitative immunohistochemistry, electron microscopy, multiplex ELISAs, mRNA analyses, and MALDI-MS. The research is novel, mechanistic, robust, transparent, and inclusive of dose effects and both sexes. The prospects for extending this research to humans via non-invasive MALDI EV assays are extremely high.


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 = $330,075 )
2024	2024	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Alcohol Research Programs	000	25	3/26/2024	NON-COMPETING CONTINUATION	$330,075
														Subtotal = $330,075

Issue Date FY: 2023 ( Subtotal = $366,750 )
2023	2023	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Alcohol Research Programs	000	24	4/14/2023	NON-COMPETING CONTINUATION	$366,750
														Subtotal = $366,750

Issue Date FY: 2022 ( Subtotal = $366,750 )
2022	2022	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Alcohol Research Programs	000	23	3/31/2022	NON-COMPETING CONTINUATION	$366,750
														Subtotal = $366,750

Issue Date FY: 2021 ( Subtotal = $361,589 )
2021	2021	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Alcohol Research Programs	000	22	5/10/2021	COMPETING CONTINUATION	$361,589
														Subtotal = $361,589

Issue Date FY: 2009 ( Subtotal = $330,137 )
2009	2009	RHODE ISLAND HOSPITAL	593 EDDY ST, ALDRICH 317	PROVIDENCE	RI	02903	PROVIDENCE	USA	Alcohol Research Programs	000	12	7/29/2009	COMPETING CONTINUATION	$330,137
														Subtotal = $330,137

Issue Date FY: 2007 ( Subtotal = $292,039 )
2007	2007	RHODE ISLAND HOSPITAL	593 EDDY ST, ALDRICH 317	PROVIDENCE	RI	02903	PROVIDENCE	USA	Alcohol Research Programs	000	11	3/7/2007	NON-COMPETING CONTINUATION	$292,039
														Subtotal = $292,039

Issue Date FY: 2006 ( Subtotal = $300,762 )
2006	2006	RHODE ISLAND HOSPITAL	593 EDDY ST, ALDRICH 317	PROVIDENCE	RI	02903	PROVIDENCE	USA	Alcohol Research Programs	000	10	3/21/2006	NON-COMPETING CONTINUATION	$300,762
														Subtotal = $300,762

Issue Date FY: 2005 ( Subtotal = $308,000 )
2005	2005	RHODE ISLAND HOSPITAL	593 EDDY ST, ALDRICH 317	PROVIDENCE	RI	02903	PROVIDENCE	USA	Alcohol Research Programs	000	9	3/14/2005	NON-COMPETING CONTINUATION	$308,000
														Subtotal = $308,000

Issue Date FY: 2004 ( Subtotal = $308,000 )
2004	2004	RHODE ISLAND HOSPITAL	593 EDDY ST, ALDRICH 317	PROVIDENCE	RI	02903	PROVIDENCE	USA	Alcohol Research Programs	000	8	3/15/2004	NON-COMPETING CONTINUATION	$308,000
														Subtotal = $308,000

Issue Date FY: 2003 ( Subtotal = $308,000 )
2003	2003	RHODE ISLAND HOSPITAL	593 EDDY ST, ALDRICH 317	PROVIDENCE	RI	02903	PROVIDENCE	USA	Alcohol Research Programs	000	7		COMPETING CONTINUATION	$308,000
														Subtotal = $308,000

Issue Date FY: 2000 ( Subtotal = $219,108 )
2000	2000	RHODE ISLAND HOSPITAL	593 EDDY ST, ALDRICH 317	PROVIDENCE	RI	02903	PROVIDENCE	USA	Alcohol Research Programs	000	6	8/9/2000	NON-COMPETING CONTINUATION	$219,108
														Subtotal = $219,108

Issue Date FY: 1999 ( Subtotal = $210,681 )
1999	1999	RHODE ISLAND HOSPITAL	593 EDDY ST, ALDRICH 317	PROVIDENCE	RI	02903	PROVIDENCE	USA	Alcohol Research Programs	000	5	7/31/1999	NON-COMPETING CONTINUATION	$210,681
														Subtotal = $210,681

Issue Date FY: 1998 ( Subtotal = $212,471 )
1998	1998	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Alcohol Research Programs	000	3	8/11/1998	NON-COMPETING CONTINUATION	$212,471
														Subtotal = $212,471

Grand Total All Awards = $3,914,362

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FASD Inhibition of ASPH-Notch Mediates Adolescent Cerebral White Matter Pathology-Potential Utility of Non-invasive Extracellular Vesicle Assays

Award Number: R01AA011431

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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