# Modeling patient mutations in iPSC-derived neurons to reveal cellular mechanisms of schizophrenia

> **NIH NIH K08** · UNIVERSITY OF WASHINGTON · 2022 · $187,488

## Abstract

Schizophrenia is a common and devastating neurodevelopmental disorder that has defied diagnostic and
therapeutic advances due to its complex pathogenesis and genetic heterogeneity. Experimental approaches that
integrate genetics and biology are necessary to further our understanding of this complex disorder. Both common
genetic variants of small effect and rare genetic mutations of severe effect have been implicated in schizophrenia,
with the latter more likely to produce phenotypes that can be measured in vitro.
This proposal describes a 5-year career development program through which I will develop the conceptual
framework and gain the skills necessary to characterize rare, severe mutations in persons with schizophrenia.
My project will be to evaluate, using CRISPR-interference (CRISPRi) in iPSCs, genes that share 3 criteria: 1)
each gene harbors a damaging mutation in one or more patients from our studies; 2) each gene is significantly
associated with schizophrenia per criteria of the SCHEMA consortium; and 3) each gene plays a role in chromatin
remodeling or transcriptional regulation.
In Aim 1, I will use CRISPRi to knock down expression of each of these genes in iPSC-derived neurons, then
compare transcriptional signatures before and after loss of gene expression, and to other iPSC models of
schizophrenia. I will also assay for changes in cellular oxidative stress, a cellular phenotype of iPSC models of
schizophrenia.
In Aim 2, I will generate a patient-derived iPSC line for one of the genes from Aim 1, then create an isogenic
iPSC line with the reversion to wild-type of the mutation using CRISPR-mediated homology directed repair.
(Lymphoblast lines of all patients from Aim 1 are available for this purpose.) I will compare patient and revertant
iPSCs with the same assays as in Aim 1, and also for their ability to form mature neurons, their neurite number,
cellular migration defects, transcriptional profiles, and epigenetic effects.
In Aim 3, from my clinic, I will enroll additional patient-parent-parent trios; collect blood for DNA, RNA, and the
establishment of cell lines; organize the collection of longitudinal clinical data; and carry out exome sequencing
and identify damaging variants for my future studies. I have obtained approval of this aim from the UW IRB.
This K08 award will provide me with the mentorship and conceptual and experimental training necessary for
each of these approaches. My overall goal is to establish my independent laboratory studying the genes
responsible for the pathophysiology of schizophrenia.

## Key facts

- **NIH application ID:** 10488719
- **Project number:** 5K08MH126171-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Anna Brosius Sunshine
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $187,488
- **Award type:** 5
- **Project period:** 2021-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10488719

## Citation

> US National Institutes of Health, RePORTER application 10488719, Modeling patient mutations in iPSC-derived neurons to reveal cellular mechanisms of schizophrenia (5K08MH126171-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10488719. Licensed CC0.

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