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

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $922,880

## Abstract

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.

## Key facts

- **NIH application ID:** 10818433
- **Project number:** 5R01MH130441-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Jason Louis Stein
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $922,880
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10818433

## Citation

> US National Institutes of Health, RePORTER application 10818433, IBIS-iPSC: Organoid modeling of cortical surface area hyperexpansion in autism spectrum disorder (5R01MH130441-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10818433. Licensed CC0.

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