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IBIS-iPSC: Organoid modeling of cortical surface area hyperexpansion in autism spectrum disorder

Award Number: R01MH130441
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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IBIS-iPSC: Organoid modeling of cortical surface area hyperexpansion in autism spectrum disorder - Project Summary/Abstract Many individuals with monogenic and idiopathic forms of autism spectrum disorder (ASD) exhibit brain enlargement early in life. However, the underlying cellular and molecular mechanisms leading to early brain overgrowth in ASD are unknown. To identify the mechanisms leading to brain overgrowth, we will use an appropriate model system, iPSC-derived organoids, from a well-powered, deeply phenotyped cohort with multiple control groups, the Infant Brain Imaging Study (IBIS). IBIS is the largest longitudinal neuroimaging study of infants (>250 participants) at high familial risk for autism by virtue of having an older sibling/proband with ASD. Importantly, IBIS participants have previously undergone longitudinal neuroimaging at multiple time points in infancy (between 6-24 months of age) and school age, extensive behavioral assessments at these time points, as well as rare and common variant genotyping. The extensive phenotypic data generated in this cohort make it an ideal population from which to generate iPSC-derived organoid models and relate in vitro phenotypes to in vivo brain growth and behavioral trajectories. Our study also represents a unique opportunity to evaluate how well organoid phenotypes model the in vivo brain growth trajectories of the individual from whom they were derived. In this proposal, we will derive and validate iPSCs from blood for participants from high risk families who developed ASD (HR+), high risk participants who did not develop ASD (HR-), and low risk individuals without ASD (LR-) totaling 99 participants. We will differentiate the iPSC lines to cortical organoids to model inter- individual differences in brain development. We will use single cell (sc)RNA-seq to identify cell types, cell cycle states, and differentiation trajectories in each participant-derived organoid across two time points modeling the period of cortical neurogenesis, totaling 2.38M sequenced cells. We will validate cell type counts and states using tissue clearing followed by lightsheet microscopy of the cortical organoids. We will identify cell types, fate decisions, and cell cycle states that correlate with both cross-sectional and longitudinal cortical surface area growth and ASD symptoms and cognitive ability over time. Leveraging this unique, deeply characterized clinical cohort, we will determine both the in vivo relevance of cortical organoids and the cellular and molecular mechanisms underlying brain overgrowth in 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: 2026 ( Subtotal = $752,255 )
2026	2026	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Mental Health Research Grants	000	4	1/16/2026	NON-COMPETING CONTINUATION	$752,255
														Subtotal = $752,255

Issue Date FY: 2025 ( Subtotal = $606,258 )
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Mental Health Research Grants	000	3	1/24/2025	NON-COMPETING CONTINUATION	$606,258
														Subtotal = $606,258

Issue Date FY: 2024 ( Subtotal = $922,880 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Mental Health Research Grants	000	2	4/5/2024	NON-COMPETING CONTINUATION	$830,592
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Mental Health Research Grants	001	2	8/14/2024	NON-COMPETING CONTINUATION	$92,288
														Subtotal = $922,880

Issue Date FY: 2023 ( Subtotal = $859,996 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Mental Health Research Grants	000	1	3/31/2023	NEW	$859,996
														Subtotal = $859,996

Grand Total All Awards = $3,141,389

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IBIS-iPSC: Organoid modeling of cortical surface area hyperexpansion in autism spectrum disorder

Award Number: R01MH130441

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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