# Construction of the integrated human cortical organoids to investigate neurodevelopmental disorders

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $638,977

## Abstract

Project Summary
Diagnosed mainly based on symptomatic description, it is difficult to distinguish the underlying mechanisms of
neuropsychiatric disorders, including schizophrenia (SCZ) and autism spectrum disorders (ASD). Recent
advanced human genetic studies have identified the genetic underpinning of the a variety of neuropsychiatric
disorders, showing that majority of SCZ and ASD are genetically heterogeneous and caused by with rare de
novo mutations. Particularly, a rare mutations at SET1/COMPASS complex proteins or related proteins were
distinctly discovered at SCZ or ASD patients. Our central hypothesis is that investigating the function of SCZ-
or ASD-associated proteins in cortical and subcortical development will reveal the molecular mechanism how
mutations of proteins with similar catalytic activity result in clinically distinct disorders. The paucity of accessible
human brain tissues has been challenging to directly addressing these questions by using human brain tissue.
Thus, in order to achieve the goal, we will use human brain organoids that structually and functionally
reproduce the developing human brain regions. The use of human pluripotent stem cells (hPSCs) has
revolutionized the human brain studies. hPSCs undergo unlimited self-renewal and can differentiate into any
cell types, including brain cells. We have reported the generation of 3-dimensional (3-D) structures from
hPSCs that recapitulate the developing human cortex (hCO, cortical organoids), medial ganglionic eminence
(hMGEO, MGE organoid), or diencephalic thalamus (hThO, thalamic organoids). Fusing hCO with hMGEO, or
hThO reproduced the interaction of developmentally distinct two regions, such as tangential migration of MGE
cells to cortex, or reciprocal corticothalamic or thalamocortical connections. Using the advanced stem cell
tools, we will purse the aims to achieve the goal. 1) We will use CRISPR/CAS9 gene editing tools to introduce
mutations of SCZ and ASD genes into hPSC lines, and investigate the cellular and molecular function in
cortical and thalamic development using hThOs and hCOs. 2) We will develop methods to reproduce the
multiple nuclei in thalamus to further improve the regional specification of hThOs. 3) We will investigate the
function of SCZ and ASD genes in cortical and subcortical connectivity. Overall, our advanced human brain
organoid-based approaches combined with genomics and neurobiological tools will define the molecular
mechanism distinctly regulated by SCZ and ASD-associated genes and provide unprecedented unique
platforms to construct the functional corticothalamic connection.

## Key facts

- **NIH application ID:** 10216628
- **Project number:** 5R01MH118344-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** In-Hyun Park
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $638,977
- **Award type:** 5
- **Project period:** 2019-09-09 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10216628

## Citation

> US National Institutes of Health, RePORTER application 10216628, Construction of the integrated human cortical organoids to investigate neurodevelopmental disorders (5R01MH118344-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10216628. Licensed CC0.

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