# Differentiation and Integration of Trisomy 21 iPSCs in an Animal Model

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2021 · $319,259

## Abstract

PROJECT SUMMARY / ABSTRACT:
 Differentiation and Integration of Trisomy 21 iPSCs into Cerebral Tissues: Modeling Down
Syndrome using Patient-specific iPSC-derived CNS Organoids and Humanized Chimeric Mice. Down
syndrome (DS) is caused by trisomy 21, the triplication of human chromosome 21 (HSA21), and is the most
common genetic cause of intellectual disability. We have successfully established and characterized multiple
lines of iPSCs derived from DS patients. Particularly, we have established more than 50 DS Trisomy 21 iPSC
lines, and obtained multiple pairs of corresponding isogenic disomy 21 control lines from these DS iPSCs. In
addition, we have implemented CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic
Repeats/CRISPR-associated) technology in making genetic corrections in iPSCs. Modeling of human genetic
diseases has previously been largely dependent upon availability of either pathological analysis of postmortem
human tissue samples or recapitulation of human disease in transgenic animal models; better research tools
for disease modeling are needed. Patient-specific iPSCs are excellent tools and versatile resources for this
kind of translational research. As iPSCs are generated on an individual basis, iPSCs may be the optimal
cellular material to use for disease modeling, drug discovery, and development of patient-specific therapies.
We have already generated a significant amount of preliminary data. We have used a highly efficient CRSPR
system to precisely control and normalize genes of interest on HSA21. We have also developed a system of 3-
dimentional (3D) CNS organoid (CO) culture from DS iPSCs, which better recapitulates brain development and
disease pathogenesis than the conventional 2-dimentional (2D) flat culture, and allows for in-depth
characterization by electrophysiological assays. The CNS organoid technology represents an excellent
approach for disease modeling; the cerebral organoids generated from patient iPSCs can be used as a model
to recapitulate complex neural developmental diseases such as DS. In addition, we have generated a
humanized chimeric mouse model, in which DS iPSC derived astrocytes are grafted to the neonatal mouse
brains. The detailed genetic etiology for the various symptoms in DS remains elusive. Taking the advantage of
these unique tools and resources, we will create novel in vitro and in vivo models of DS with human iPSCs
derived from patients to recapitulate the defects in neural differentiation in DS. In support of the feasibility of
this proposal, we have obtained the necessary materials and expertise to be used in this study, and have
published a rather massive paper on DS iPSCs [Chen C, Jiang P, Xue H, Peterson SE, Tran HT, McCann AE,
Parast MM, Li S, Pleasure DE, Laurent LC, Loring JF, Liu Y, Deng W. (2014) Role of astroglia in Down’s
syndrome revealed by patient-derived human-induced pluripotent stem cells. Nature Communications. 5:4430
doi: 10.1038/ncomms5430 (2014)]. Our prelimin...

## Key facts

- **NIH application ID:** 10142515
- **Project number:** 5R01HD091325-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Lin Tian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $319,259
- **Award type:** 5
- **Project period:** 2017-08-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10142515

## Citation

> US National Institutes of Health, RePORTER application 10142515, Differentiation and Integration of Trisomy 21 iPSCs in an Animal Model (5R01HD091325-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10142515. Licensed CC0.

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