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Investigating the roles of UBE3A and TRPML1 in extracellular vesicle regulation to understand Angelman syndrome pathogenesis

Award Number: R15MH101703
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2014
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Investigating the roles of UBE3A and TRPML1 in extracellular vesicle regulation to understand Angelman syndrome pathogenesis - Brain development is a complex process involving intricate molecular interactions, which lead to alterations at the synaptic, neuronal, and circuit levels. Abnormalities in this process result in various forms of neurodevelopmental disorders. Angelman syndrome (AS) is a rare neurodevelopmental disorder with severe developmental delay, lack of language skills, severe cognitive impairment, motor dysfunction, and often with comorbid epilepsy and autism spectrum disorder (ASD). Genetic/genomic studies have attributed the cause of AS to deficiency of UBE3A, an imprinted gene, in neurons. Mice with maternal Ube3a deficiency recapitulate most of AS symptoms, and studies with these mouse models have revealed that Ube3a deficiency affects many brain regions and circuits. On the other hand, UBE3A overexpression or gain-of-function mutations have been linked to increased risk for autism spectrum disorders. Thus, accumulating evidence indicates that UBE3A plays critical roles in brain development and maturation. However, there is still a critical need for better understanding the roles of UBE3A during development and in adulthood. Emerging evidence also shows that the lysosomal cation channel, TRPML1, is also crucial for normal brain development and functions, since its deficiency results in a developmental neurological disease, muculipdosis type IV (MLIV). In recent years, extracellular vesicles (EVs), have been shown to play diverse roles in brain development and functions, in health and disease, through intercellular communication and transport of molecules. The proposed studies will test the hypothesis that UBE3A regulates dendritic spine development through TRPML1-mediated EV release, and that UBE3A deficiency leads to reduced EV release, resulting in abnormal dendritic spine development and maturation. The proposed studies will further test the hypothesis that treatment with EVs from wild-type neurons could rescue dendritic spine deficiency in AS neurons. The outcomes of this proposal will not only shed light on the roles of UBE3A and TRPML1 in neuronal development through the regulation of EV release but also provide novel approaches for the therapeutic treatment of AS patients. As emerging research indicates that EVs are suitable biomarkers and potential therapeutical tools for several neurological disorders, the outcomes of this proposal could have broad clinical implications.


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 = $429,000 )
2025	2025	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Mental Health Research Grants	000	4	6/19/2025	COMPETING CONTINUATION	$429,000
														Subtotal = $429,000

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Mental Health Research Grants	000	3	5/16/2024	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Mental Health Research Grants	001	3	2/28/2022	COMPETING CONTINUATION	$75,384
2022	2017	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Mental Health Research Grants	000	2	2/28/2022	COMPETING CONTINUATION	-$75,384
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $423,000 )
2021	2021	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Mental Health Research Grants	001	3	5/10/2021	COMPETING CONTINUATION	$423,000
2021	2017	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Mental Health Research Grants	000	2	5/10/2021	COMPETING CONTINUATION	$0
														Subtotal = $423,000

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2017	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Mental Health Research Grants	001	2	12/13/2017	COMPETING CONTINUATION	$56,845
2018	2014	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Mental Health Research Grants	000	1	12/13/2017	NEW	-$56,845
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $423,000 )
2017	2017	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Mental Health Research Grants	000	2	7/18/2017	COMPETING CONTINUATION	$423,000
														Subtotal = $423,000

Issue Date FY: 2014 ( Subtotal = $425,708 )
2014	2014	WESTERN UNIVERSITY OF HEALTH SCIENCES	COLLEGE PLAZA	POMONA	CA	91766	LOS ANGELES	USA	Mental Health Research Grants	000	1	7/18/2014	NEW	$425,708
														Subtotal = $425,708

Grand Total All Awards = $1,700,708

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Investigating the roles of UBE3A and TRPML1 in extracellular vesicle regulation to understand Angelman syndrome pathogenesis

Award Number: R15MH101703

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2014

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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