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Understanding the Role of Epac2 in Cognitive Function

Award Number: F30MH096457
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/01/2013
PERIOD OF PERFORMANCE END DATE: 02/29/2016

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Understanding the Role of Epac2 in Cognitive Function - DESCRIPTION (provided by applicant): Dendritic spines are tiny protrusions on dendrites and are the sites of most excitatory synapses in the mammalian brain. Spines can be rapidly formed, eliminated, or change size/shape in response to stimuli~ this spine plasticity contributes to numerous physiological processes such as synaptic transmission and plasticity. Conversely, abnormal spine structure, dynamics, and function are important contributors to the pathogenesis of numerous neuropsychiatric disorders, including Autism Spectrum Disorders (ASD). ASD are a group of neurodevelopmental disorders that are characterized by social deficits, communication difficulties, and repetitive behaviors. As part of an effort to understand the genetic etiologies of ASD, four independent genome studies of ASD patients have localized the chromosome region 2q31-32 as a hotspot for genes relevant to the disease. A screen for candidate ASD genes in this chromosomal region revealed exclusive single amino-acid variants in the EPAC2 gene that segregate exclusively with autistic family members but not unaffected controls. Epac2 is a guanine nucleotide exchange factor that modulates the small GTPase Rap, a known regulator of spine structure and function. Our lab has shown that several of the identified Epac2 autism- associated variants (Epac2-AAVs) cause altered Rap activity as well as aberrant dendritic spine morphologies in vitro. In addition, we found that EPAC2-deficient mice have altered spine dynamics in vivo. Collectively, this data suggests that aberrant Rap signaling, via dysfunctional Epac2 activity, may lead to abnormal spine morphogenesis in vivo. However, as little is known about the role of Epac2 at synapses, understanding Epac2's mechanism in signaling and in regulating downstream spine plasticity is essential. In this proposal, we aim to gain a mechanistic understanding of the Epac2 signaling complex and how Epac2-AAVs may affect the complex's structure and function. Preliminary data from our lab show that Epac2 is in a complex with two post- synaptic scaffolding proteins, Shank3 and PSD95. We will thus perform in vitro binding assays to determine the nature of the interactions between these three proteins. We will then determine how Shank3/PSD-95 affects Epac2/Epac2-AAVs function by comparing the effects of Epac2/Epac2-AAVs, in the presence of PSD- 95/Shank3, on downstream Rap activity and by characterizing Epac2/Epac2-AAVs localization patterns in the presence of PSD-95/Shank3. We also intend to gain a deeper insight into Epac2's downstream physiological relevance to spine plasticity by determining how Epac2 modulates spine dynamics throughout postnatal development in vivo. We will use intravital two-photon microscopy to image dendritic spines in EPAC2-deficient mice of various ages and will perform pharmacological rescue experiments to reverse synaptic alterations. In conclusion, our work may explain how Epac2 dysfunction contributes to the complicated neurobiology of ASD.


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: 2020 ( Subtotal = -$1,577 )
2020	2015	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Mental Health Research Grants	000	3	5/14/2020	NON-COMPETING CONTINUATION	-$1,577
														Subtotal = -$1,577

Issue Date FY: 2017 ( Subtotal = -$12,316 )
2017	2015	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Mental Health Research Grants	000	3	1/30/2017	NON-COMPETING CONTINUATION	-$12,316
														Subtotal = -$12,316

Issue Date FY: 2016 ( Subtotal = $48,576 )
2016	2016	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Mental Health Research Grants	000	4	2/27/2016	EXTENSION WITH OR WITHOUT FUNDS	$48,576
														Subtotal = $48,576

Issue Date FY: 2015 ( Subtotal = $48,120 )
2015	2015	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Mental Health Research Grants	000	3	2/9/2015	NON-COMPETING CONTINUATION	$48,120
														Subtotal = $48,120

Issue Date FY: 2014 ( Subtotal = $47,676 )
2014	2014	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Mental Health National Research Service Awards for Research Training	000	2	2/25/2014	NON-COMPETING CONTINUATION	$47,676
														Subtotal = $47,676

Issue Date FY: 2012 ( Subtotal = $47,232 )
2012	2012	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Mental Health National Research Service Awards for Research Training	000	1	9/3/2012	NEW	$47,232
														Subtotal = $47,232

Grand Total All Awards = $177,711

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Understanding the Role of Epac2 in Cognitive Function

Award Number: F30MH096457

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/01/2013

PERIOD OF PERFORMANCE END DATE: 02/29/2016

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