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Interagency Autism Coordinating Committee (IACC)
Autism Research Database
Office of Autism Research Coordination (OARC)
 
Project Element Element Description

Project Title

Project Title

Functional and anatomical recovery of synaptic deficits in a mouse model of Angelman Syndrome

Principal Investigator

Principal Investigator

McCoy, Portia

Description

Description

Several autism spectrum disorders have been linked to dysfunction of a single gene - UBE3A. Individuals having deletions or mutations of the maternal UBE3A gene suffer from the severe intellectual disability Angelman syndrome (AS), an autism spectrum disorder, while individuals expressing two or more copies of maternal UBE3A exhibit a more classic form of autism. Thus, a major goal has been to identify mechanisms for adjusting UBE3A gene dosage, as this could be of therapeutic value. UBE3A is a relatively unique gene, in that the paternally-inherited copy is silent in most brain neurons. Thus, one therapeutic opportunity for AS is to "awaken" the dormant paternal allele. The research team has recently made the exciting discovery of small molecule compounds that can unsilence paternal Ube3a in a mouse model of AS. This study will take advantage of the well characterized synaptic deficits in AS model mice to test the therapeutic value of the lead compound. Loss of Ube3a expression has previously been shown to decrease the number of dendritic spines (synaptic sites) in the brain and alter the capacity for functional synaptic plasticity. The hypothesis that pharmacological unsilencing of paternal Ube3a will recover functional and structural plasticity of synapses in AS model mice during critical periods of brain development will be tested in this study. To date, nothing is known about the effect of unsilencing imprinted genes and whether this is a valuable therapeutic option. By filling this gap in knowledge, my studies will begin therapeutic testing of UNCilencer1, helping to lead the way into human clinical trials. These studies will afford the Fellow the opportunity to learn several new techniques, including in vivo, high-resolution microscopy combined with pharmacological manipulations. In addition to the basic science that will be performed, the Fellow will be attending, contributing, and learning from AS and drug trial patient clinics. The studies and training plan will allow the Fellow to better bridge the gap between the animal model testing and application to human patients. Ultimately this cross-disciplinary training will lead to a career that is both highly collaborative and highly translational, with a focus on developing autism therapeutics.

Funder

Funder

Autism Speaks

Fiscal Year Funding

Fiscal Year Funding

56000

Current Award Period

Current Award Period

2012-2014

Strategic Plan Question

Strategic Plan Question

Question 2: How Can I Understand What Is Happening?

Strategic Plan Objective

Strategic Plan Objective

Green dot: Objective has greater than or equal to the recommended funding. 2SD. Launch three studies that target improved understanding of the underlying biological pathways of genetic conditions related to autism (e.g. Fragile X, Rett syndrome, tuberous sclerosis complex) and how these conditions inform risk assessment and individualized intervention by 2012. IACC Recommended Budget: $9,000,000 over 5 years.

Project Link

Project Link

Functional and anatomical recovery of synaptic deficits in a mouse model of Angelman Syndrome (External web link)

Institution

Institution

University of North Carolina at Chapel Hill

State/Country

State/Country

North Carolina

Project Number

Project Number

7612

Federal or Private?

Federal or Private?

Private

Received ARRA Funding?

Received ARRA Funding?

No

History/Related Projects

History/Related Projects

Functional and anatomical recovery of synaptic deficits in a mouse model of Angelman Syndrome | 0 | 2014 | 7612
Functional and anatomical recovery of synaptic deficits in a mouse model of Angelman Syndrome | 58000 | 2013 | 7612

 
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