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Regulation of mTOR signaling in the developing cerebral cortex as a point of convergence for multiple autism risk factors

Award Number: R01MH108519
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT Signaling through mTOR is a critical regulator of protein synthesis in the developing brain, and numerous autism spectrum disorder (ASD) and intellectual disability (ID) risk genes have been identified that impinge on mTOR signaling and cause altered growth and connectivity at the level of brain areas/circuits or individual cell types. Mutations in dual-specificity tyrosine phosphorylation-regulated kinase 1a (DYRK1A) cause microcephaly and neuronal undergrowth in a subset of individuals with ASD and ID, as well as in mouse models. The mechanisms by which mutations in DYRK1A lead to microcephaly and ASD/ID are unknown but are critical to identify for the development of targeted treatments. Given the observations that multiple ASD risk genes that impact overall brain growth exhibit altered mTOR signaling and that decreased mTOR signaling in the developing cerebral cortex has been linked with microcephaly, pyramidal neuron undergrowth and deficits in behavior and cognition, we are testing the hypothesis that DYRK1A mutations cause microcephaly, neuronal undergrowth and ASD-relevant behavioral deficits through dysregulated mTOR signaling. Preliminary data collected during the previous funding period indicate that mTOR signaling is downregulated in the developing cerebral cortex of Dyrk1a mutant mice, and that upregulation of mTOR signaling via genetic suppression of Pten or pharmacological treatment with IGF-1 can rescue microcephaly and neuronal undergrowth in this model. The two aims of this proposal are designed to: 1) profile the effects of cerebral cortical Dyrk1a mutations on neuroanatomical and behavioral phenotypes relevant to the DYRK1A clinical population and to dysregulated mTOR signaling, and 2) test the hypothesis that Dyrk1a and mTOR signaling act in a common regulatory network to influence ASD-relevant brain growth and behavioral phenotypes. Completion of this project will elucidate molecular and cellular mechanisms of microcephaly, neuronal undergrowth and ASD-relevant behavioral deficits caused by mutations in DYRK1A and other ASD/ID risk genes that impinge on the mTOR pathway and will guide the development of treatments for the DYRK1A clinical population.


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: 2023 ( Subtotal = $462,500 )
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Mental Health Research Grants	000	9	6/6/2023	NON-COMPETING CONTINUATION	$462,500
														Subtotal = $462,500

Issue Date FY: 2022 ( Subtotal = $462,500 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Mental Health Research Grants	002	8	6/10/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$172,080
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Mental Health Research Grants	005	8	8/29/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$12,435
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Mental Health Research Grants	001	7	6/9/2022	NON-COMPETING CONTINUATION	-$125,830
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Mental Health Research Grants	004	7	8/29/2022	NON-COMPETING CONTINUATION	-$12,435
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Mental Health Research Grants	003	7	6/13/2022	NON-COMPETING CONTINUATION	$0
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Mental Health Research Grants	000	7	2/15/2022	NON-COMPETING CONTINUATION	$416,250
														Subtotal = $462,500

Issue Date FY: 2021 ( Subtotal = $462,500 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Mental Health Research Grants	000	6	4/26/2021	COMPETING CONTINUATION	$462,500
2021	2020	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Mental Health Research Grants	001	5	9/9/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $462,500

Issue Date FY: 2020 ( Subtotal = $480,000 )
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Mental Health Research Grants	000	5	4/15/2020	NON-COMPETING CONTINUATION	$480,000
														Subtotal = $480,000

Issue Date FY: 2019 ( Subtotal = $480,000 )
2019	2019	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Mental Health Research Grants	000	4	3/6/2019	NON-COMPETING CONTINUATION	$480,000
														Subtotal = $480,000

Issue Date FY: 2018 ( Subtotal = $480,000 )
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Mental Health Research Grants	001	3	6/15/2018	NON-COMPETING CONTINUATION	$48,000
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Mental Health Research Grants	000	3	3/22/2018	NON-COMPETING CONTINUATION	$432,000
														Subtotal = $480,000

Issue Date FY: 2017 ( Subtotal = $480,000 )
2017	2017	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Mental Health Research Grants	000	2	3/6/2017	NON-COMPETING CONTINUATION	$432,000
2017	2017	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Mental Health Research Grants	001	2	8/10/2017	NON-COMPETING CONTINUATION	$48,000
														Subtotal = $480,000

Issue Date FY: 2016 ( Subtotal = $480,000 )
2016	2016	SCRIPPS RESEARCH INSTITUTE-FLORIDA	10550 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Mental Health Research Grants	000	1	6/24/2016	NEW	$480,000
														Subtotal = $480,000

Grand Total All Awards = $3,787,500

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Regulation of mTOR signaling in the developing cerebral cortex as a point of convergence for multiple autism risk factors

Award Number: R01MH108519

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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