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PROTEOMICS IN DROSOPHILA TO IDENTIFY AUTISM CANDIDATE SUBSTRATES OF UBE3A

Award Number: R01NS059902
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2008
PERIOD OF PERFORMANCE END DATE: 08/31/2012

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PROTEOMICS IN DROSOPHILA TO IDENTIFY AUTISM CANDIDATE SUBSTRATES OF UBE3A - DESCRIPTION (provided by applicant): Autism spectrum disorders (ASD) affect ~60 in 10,000 children but in only ~10% of these individuals is autism associated with a recognized cause. Understanding the molecular pathways dysregulated in Angelman syndrome (AS), a rare and severe developmental disorder related to autism, may provide key insights leading to identification of autism susceptibility genes and pathways. Approximately 3% of all autism cases result from maternal duplications of the region containing the AS gene UBE3A. Variants in genes encoding protein targets of the ubiquitin ligase UBE3A may, therefore, confer a genetic susceptibility to autism or even cause an ASD phenotype. Here we describe a proteomics strategy utilizing the powerful genetic model organism Drosophila melanogaster to identify protein targets of human UBE3A and fly Dube3a. UBE3A will be over-expressed in the brains of flies using the GAL4/UAS system in order to increase or decrease the levels of UBE3A/Dube3a protein targets. We will then identify these targets by Rotofor-assisted proteomic profiling and mass spectrometry. Potential targets will be validated though genetic interactions in the eye and neuromuscular junction, binding assays in 293T cells and immunohistochemistry in the brains of both Ube3a-deficient and over-expressing mice. We anticipate that these studies will provide us with new autism candidate genes for future validation in families that demonstrate heritable autism risk. To this end, we propose the following specific aims: Specific Aim 1: To identify potential UBE3A and Dube3a regulated proteins using proteomic profiling in Drosophila head extracts. Completion of this aim will result in a collection of potential Dube3a and UBE3A regulated proteins for subsequent validation and autism genetic studies. Specific Aim 2: To validate physical, biochemical and genetic interactions between potential targets and Dube3a. This aim will test the hypothesis that the proteins detected in Aim #1 are regulated directly or indirectly by Dube3a. Specific Aim 3: To determine if UBE3A regulated protein expression patterns are altered in the brains of Ube3a deficient and over-expression mice. This aim will demonstrate a link between Ube3a target proteins and altered brain function in the mouse models of Angelman syndrome and proximal 15q duplication autism. PUBLIC HEALTH RELEVANCE: The primary goal of this research is to identify proteins regulated by UBE3A and to investigate the possibility that these proteins are also dysregulated or mutated in some cases of autism. Understanding how increased levels of UBE3A result in an autism phenotype at the molecular level will help us better identify and treat the underlying liability in idopathic autism.


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: 2011 ( Subtotal = $342,759 )
2011	2011	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	8/16/2011	NON-COMPETING CONTINUATION	$313,159
2011	2011	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	7/5/2011	SUPPLEMENT FOR EXPANSION	$29,600
														Subtotal = $342,759

Issue Date FY: 2010 ( Subtotal = $316,355 )
2010	2010	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	9/15/2010	NON-COMPETING CONTINUATION	$316,355
														Subtotal = $316,355

Issue Date FY: 2009 ( Subtotal = $321,325 )
2009	2009	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	2	8/18/2009	SUPPLEMENT FOR EXPANSION	$10,000
2009	2009	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	2	8/11/2009	NON-COMPETING CONTINUATION	$319,550
2009	2008	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	12/24/2008	NEW	$313,338
2009	2008	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	12/17/2008	NEW	-$313,338
2009	2008	UNIVERSITY OF TENNESSEE CENTER FOR THE HEALTH SCIENCES	62 SOUTH DUNLAP STREET	MEMPHIS	TN	38103	SHELBY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	10/22/2008	NEW	-$8,225
														Subtotal = $321,325

Issue Date FY: 2008 ( Subtotal = $321,563 )
2008	2008	UNIVERSITY OF TENNESSEE	WEST CUMBERLAND AVENUE, SW	KNOXVILLE	TN	37916	KNOX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/26/2008	NEW	$321,563
														Subtotal = $321,563

Grand Total All Awards = $1,302,002

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PROTEOMICS IN DROSOPHILA TO IDENTIFY AUTISM CANDIDATE SUBSTRATES OF UBE3A

Award Number: R01NS059902

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2008

PERIOD OF PERFORMANCE END DATE: 08/31/2012

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