# Creation and Evaluation of iPSCs from Children with ASD with Megalencephaly

> **NIH NIH P50** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $382,928

## Abstract

PROJECT SUMMARY – PROJECT 3
Autism spectrum disorder (ASD) is a complex condition characterized by important changes to the brain and
behavior. 15% of boys with ASD have disproportionate megalencephaly (ASD-DM), or enlarged brain relative to
body size. An increase in brain size often precedes the first clinical signs of the disorder, suggesting that
understanding the mechanisms leading to brain overgrowth could provide a window of opportunity to intervene
and possibly prevent disease onset. Here, the research team will use human induced pluripotent stem cell
(hiPSC) technology to model ASD-DM and investigate the underlying cellular and molecular mechanisms
involved. They will obtain skin fibroblasts from 40 individuals in Project 2 and derive human iPSCs from: A) 10
ASD subjects with megalencephaly, ASD-DM; B) 10 ASD subjects with normal sized brains, ASD-N C) 10
Typically developing (TD) subjects with megalencephaly, TD-DM, and D) 10 TD subjects with normal sized
brains, TD-N. Following iPSC generation, they will differentiate each of the iPSC lines into neural progenitor
cells (NPCs), oligodendrocyte progenitor cells (OPCs), and microglia (the primary immune cells in the brain that
maintain homeostasis). The overarching goals of their project are two-fold: 1) to investigate whether ASD-DM
is due to an increase in cell proliferation, increase in cell survival, improper elimination of damaged cells, and/or
a combination of all; and 2) to identify therapeutic targets by understanding the underlying cellular and signaling
mechanisms involved. In Specific Aim 1, they will identify the cellular mechanisms underlying ASD-DM by
investigating changes in the cell cycle, cell proliferation, and apoptosis of iPSC-derived NPCs, OPCs, and
microglial cells. In Specific Aim 2, they will investigate the functional activity of microglia in ASD-DM by directly
differentiating each of the iPSC lines into microglia and assessing their phagocytic capacity by co-culturing them
with mixed neuroglial cultures derived from the same lines. This will test their hypothesis that microglia are
compromised in ASD-DM, failing to eliminate damaged cells and synapses and contributing to brain overgrowth.
In Specific Aim 3, they will identify the underlying regulatory signaling mechanisms that lead to the changes at
the cellular level. They will differentiate the iPSCs into NPCs, OPCs, and microglia, sort them by flow cytometry
using antibodies specific for each cell type, and perform RNA-sequencing to identify gene networks and signaling
mechanisms that are significantly regulated in each condition. Using these mechanistic insights, they will identify
therapeutic targets to directly test in the in vitro models. Their overall goal across the projects is to collect imaging,
behavioral, and mechanistic data on the same cohort of subjects. In Specific Aim 4, they will correlate the cellular
and mechanistic data obtained in Project 3 with the imaging and behavioral data from Project 2...

## Key facts

- **NIH application ID:** 9984474
- **Project number:** 5P50HD093079-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** JOACHIM F HALLMAYER
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $382,928
- **Award type:** 5
- **Project period:** 2017-09-07 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9984474

## Citation

> US National Institutes of Health, RePORTER application 9984474, Creation and Evaluation of iPSCs from Children with ASD with Megalencephaly (5P50HD093079-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9984474. Licensed CC0.

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