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Delineating contributions of PI3K signaling to neurodevelopmental consequences of Pten haploinsufficiency

Award Number: R21NS121951
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract Autism spectrum disorder (ASD) is a remarkably heterogeneous collection of conditions that converge on the symptoms of social and communication difficulties, together with restricted interests and repetitive behavior. Underlying this heterogeneity is likely a variety of etiologies. Thus, it has become clear in recent years that a “one-size-fits-all” approach to treating ASD is not sufficient. Rather, stratifying individuals based on particular risk factors and symptoms is increasingly being explored as a way to develop targeted personalized treatments for ASD. One risk factor that is receiving significant attention in this context is mutations in the gene PTEN, which encodes a key regulator of growth in the developing body and brain. Germline heterozygous mutations in this gene, which generally reduce levels of PTEN protein, are common in individuals with ASD and macrocephaly (overgrowth of the head and brain). Our laboratory has shown that mice carrying equivalent mutations in Pten display both brain overgrowth and social behavioral deficits, establishing that a reduction in Pten protein level is sufficient to cause ASD-relevant symptoms in an animal model. Pten encodes a phosphatase that acts as a negative regulator of the enzyme phosphoinositide 3-kinase (PI3K), and dysregulation of the PI3K-Akt-mTOR pathway has been linked with neurodevelopmental pathobiology across a variety of preclinical models of ASD. Much attention has been given to inhibition of mTOR, and in particular mTOR complex 1 (mTORC1), as a strategy for treating the neurodevelopmental phenotypes arising from mutations in PTEN and other regulators of the PI3K-Akt-mTOR pathway. In contrast, the therapeutic potential of PI3K inhibition is underexplored, and has not been tested in validated in vivo preclinical models of Pten haploinsufficiency. This project aims to address this problem and to delineate the contributions of PI3K signaling to neurodevelopmental phenotypes resulting from Pten haploinsufficiency. Our overarching hypothesis is that treatment of Pten+/- mice via PI3K inhibition during development will rescue ASD-relevant phenotypes by normalizing downstream signaling. The two aims of this proposal will test this hypothesis through genetic suppression of PI3K in Pik3ca; Pten compound mutant mice (Aim 1) and through treating Pten haploinsufficient mice with a pharmacological PI3K inhibitor at distinct time windows during development to identify a critical period for treatment (Aim 2). For both aims, robust and reproducible ASD-relevant neuroanatomical and behavioral phenotypes in Pten haploinsufficient mice will be used as readouts. Key outcomes of this work will include preclinical testing of PI3K inhibition as a potential therapeutic approach to correct the neurodevelopmental consequences of PTEN mutations and the identification of a critical period when treatment may lead to a suppression of ASD-relevant symptoms.


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 = -$61 )
2024	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/18/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$61
														Subtotal = -$61

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/9/2022	NEW	-$17,397
2023	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	11/9/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$17,397
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	6/1/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$326,610
2022	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/31/2022	NEW	-$326,610
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $508,750 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/23/2021	NEW	$508,750
														Subtotal = $508,750

Grand Total All Awards = $508,689

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Delineating contributions of PI3K signaling to neurodevelopmental consequences of Pten haploinsufficiency

Award Number: R21NS121951

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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