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Dysregulation of TRIO GEF1 activity in neurodevelopmental disorders

Award Number: R01MH133562
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Dysregulation of TRIO GEF1 activity in neurodevelopmental disorders - PROJECT SUMMARY Genetic variants in the TRIO gene increase risk for neurodevelopmental disorders (NDDs) including schizophrenia, autism, and related disorders. TRIO encodes a large protein with two guanine nucleotide exchange factor (GEF) domains for Rho family GTPases: GEF1 activates Rac1 and RhoG, and GEF2 activates RhoA. We found a cluster of variants associated with autism and intellectual disability that selectively activate or inhibit TRIO GEF1 activity. While our findings highlight the central importance of this enzyme activity for proper brain development, the molecular mechanisms by which TRIO GEF1 activity is regulated, the downstream targets of TRIO GEF1 signaling, and how these processes are disrupted by GEF1-targeting variants remain fundamental, yet unresolved questions. Answering them will reveal how variants in TRIO lead to NDDs and may inform new therapeutic interventions. Our proposal will address these questions in three Aims: Aim 1. To elucidate the mechanism of TRIO GEF1 activation. We discovered that spectrin repeats 6-9 in TRIO bind and autoinhibit its GEF1 activity and that NDD-associated variants in spectrin repeat 8 relieve this autoinhibition. A short list of receptors and kinases has been identified as known or likely TRIO GEF1 regulators, but the mechanisms by which these activators engage TRIO to activate GEF1 activity are unclear. We will use purified recombinant proteins to test how these receptors’ cytoplasmic domains and kinases impact TRIO GEF1 activity. We will also use a FRET-based activity biosensor and morphological measurements to reveal how these mechanisms contribute to Rac1/RhoG activation and neuronal development induced by receptor activation. Aim 2. To identify and characterize the neuronal signaling events regulated by TRIO GEF1 activity. We have generated mice bearing TRIO variant alleles with reduced (K1431M) or elevated (R1078Q) TRIO GEF1 activity. We will use comparative proteomics and phospho-proteomics in samples from wild-type mice versus those bearing TRIO GEF1-inhibiting or activating alleles to identify proteins, signaling events, and TRIO- interaction partners impacted by changes in TRIO GEF1 activity. We will systematically test how manipulation of these GEF1-mediated events impacts neuronal development and synaptic connectivity. Aim 3. To measure how selective changes in TRIO GEF1 activity impact neuronal development and synaptic transmission. Heterozygosity for the GEF1-defective TRIOK1431M allele causes reduced brain size and behavioral defects, consistent with our hypothesis that selective alterations in TRIO GEF1 activity compromise normal neuronal development and synaptic function. We will use quantitative histopathology and electron microscopy in mice bearing the K1431M and R1078Q variants to reveal how altered TRIO GEF1 activity impacts axon, dendritic arbor, and synapse development. Whole-cell electrophysiology and optogenetic manipulation will enable us to identify the consequences of changes in TRIO GEF1 activity on neuronal excitability, synaptic function, and circuit connectivity.


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: 2025 ( Subtotal = $832,225 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	3	6/23/2025	NON-COMPETING CONTINUATION	$832,225
														Subtotal = $832,225

Issue Date FY: 2024 ( Subtotal = $840,987 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	2	5/22/2024	NON-COMPETING CONTINUATION	$840,987
														Subtotal = $840,987

Issue Date FY: 2023 ( Subtotal = $853,878 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	1	8/18/2023	NEW	$853,878
														Subtotal = $853,878

Grand Total All Awards = $2,527,090

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Dysregulation of TRIO GEF1 activity in neurodevelopmental disorders

Award Number: R01MH133562

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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