Many disorders of mental health, including autism spectrum disorder (ASD) exhibit strong or, in some cases, exclusive, contributions from individual genomic variation. These types of genomic contribution are difficult, if not impossible, to accurately recapitulate in animal in vivo or cellular models. Human pluripotent stem cells (hPSCs) provide the opportunity to use state-of-the-art genetic tools to recreate individual genomic patterns of variation that contribute to, or cause, these disorders. In Project 1, we will develop optimized genome editing methods based on strategies previously developed in non-human models. We will engineer four fluorescent reporter and Cre driver lines (CTIP2-mCherry, GFAP-mCherry, CALB-mCherry-T2A-Cre, and GAD1-mCherry- T2A-Cre), a panel of four monogenic autism models: point mutations in MECP2, SHANK3, TSC2, and FMR1, and a panel of eight CNV autism models: reciprocal duplications and deletions at 7q11.23, 16p11.2, 17p11.2, and 15q11-13. We will also develop new strategies for haplotype exchange of hIPSC models.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19MH107367-02
Application #
9146980
Study Section
Special Emphasis Panel (ZMH1)
Project Start
Project End
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Beltrão-Braga, Patricia C B; Muotri, Alysson R (2017) Modeling autism spectrum disorders with human neurons. Brain Res 1656:49-54
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de Souza, Janaina S; Carromeu, Cassiano; Torres, Laila B et al. (2017) IGF1 neuronal response in the absence of MECP2 is dependent on TRalpha 3. Hum Mol Genet 26:270-281
Shiryaev, Sergey A; Mesci, Pinar; Pinto, Antonella et al. (2017) Repurposing of the anti-malaria drug chloroquine for Zika Virus treatment and prophylaxis. Sci Rep 7:15771
Kakaradov, Boyko; Arsenio, Janilyn; Widjaja, Christella E et al. (2017) Early transcriptional and epigenetic regulation of CD8+ T cell differentiation revealed by single-cell RNA sequencing. Nat Immunol 18:422-432

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