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Identification of metabolic alterations during cortical development in a human cellular model for 22q11.2 deletion syndrome

Award Number: R01MH128352
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 The 22q11.2 microdeletion syndrome (22q11.2 DS), is associated with ~20-fold increased risk for psychosis. Brain imaging studies have consistently demonstrated abnormal functional connectivity in the cerebral cortex. Preclinical studies using cerebral cortex neurons derived from human induced pluripotent stem cells (hiPSC), revealed mitochondrial defects, neuronal hyperexcitability and calcium signaling defects, supporting the findings of cortical circuit dysfunction. However, the exact cellular and molecular mechanisms by which the 22q11.2 deletion leads to abnormal development and function of the cerebral cortex remain to be elucidated. The 22q11.2 chromosomal region contains 9 genes associated with mitochondrial energy production. Human blood samples revealed increased glycolysis, suggesting global metabolic alterations. Despite growing evidence for mitochondrial and neuronal dysfunction in 22q11.2 DS, the metabolic and mitochondrial dysregulations present in the human developing cerebral cortex remain unknown. We will test the hypothesis that human mitochondrial defects begin in proliferating neural progenitors and impair temporal mitochondrial maturation, induce metabolic reprogramming and subsequent neuronal function defects. We hypothesize these metabolic abnormalities are less pronounced in rodent models of disease. Aim 1 will identify mitochondrial defects during cortical development in hCS and forebrain sections from a mouse model for 22q11.2 DS, using advanced microscopy and functional assays. Aim 2 will assess for metabolic alterations during cortical development in hCS and forebrain sections from a mouse model for 22q11.2 DS, using untargeted metabolomics and cell type-specific metabolic profile. Aim 3 will identify metabolic pathways as targets for therapeutic interventions by testing the rescue potential of drugs known to enhance mitochondrial function (e.g. nicotinamide riboside, resveratrol, bezafibrate). Our multidisciplinary project will identify the initial timing and the exact metabolic and mitochondrial alteration during the development of the cerebral cortex in 22q11.2 DS and pinpoint metabolic pathways for drug discovery, (ii) assess for interspecies differences, and (iii) establish in vitro human neurometabolomics assays to study other metabolic disorders of genetic or environmental etiology.


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 = $638,293 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	4	12/3/2024	NON-COMPETING CONTINUATION	$638,293
														Subtotal = $638,293

Issue Date FY: 2024 ( Subtotal = $739,914 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	3	10/25/2023	NON-COMPETING CONTINUATION	$665,922
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	001	3	7/5/2024	NON-COMPETING CONTINUATION	$73,992
														Subtotal = $739,914

Issue Date FY: 2023 ( Subtotal = $772,968 )
2023	2023	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	2	11/8/2022	NON-COMPETING CONTINUATION	$695,671
2023	2023	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	001	2	1/23/2023	NON-COMPETING CONTINUATION	$77,297
														Subtotal = $772,968

Issue Date FY: 2022 ( Subtotal = $649,040 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	1	1/18/2022	NEW	$584,137
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	001	1	6/27/2022	NEW	$64,903
														Subtotal = $649,040

Grand Total All Awards = $2,800,215

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Identification of metabolic alterations during cortical development in a human cellular model for 22q11.2 deletion syndrome

Award Number: R01MH128352

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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