Schizophrenia (SCZD) is a debilitating psychiatric disorder. While 1.1% of the population suffers from SCZD, the molecular mechanisms underlying the disease state remain unclear. Though its characteristic symptoms typically appear late in adolescence, SCZD is believed to result from abnormal neurodevelopmental processes that begin years before the onset of symptoms. We previously reprogrammed fibroblasts from SCZD patients into human induced pluripotent stem cells (hiPSCs) and subsequently differentiated these disorder-specific hiPSCs into neurons;SCZD hiPSC neurons have reduced neuronal connectivity and altered gene expression relative to controls. Because gene expression profiles of our hiPSC-derived neural cells most resemble first trimester neural tissue, we believe that hiPSC neural cells are best used to study the embryonic developmental effects that contribute to disease initiation. Childhood-onset SCZD (COS) is a rare and particularly severe form of the disorder. Because COS patients present with symptoms much earlier than adult-onset cases of SCZD, our hypothesis is that neural cells derived from patients with COS will share cellular phenotypes with those we have already reported for adult-onset SCZD, but that the phenotypes may be accelerated and/or more severe. We believe that hiPSC studies of COS are an ideal platform from which to glean mechanistic insights into the early cellular and molecular factors responsible for disease initiation in SCZD. We have four primary goals for this BRAINS R01. First, we will generate hiPSC-based models of COS. Second, the cellular phenotypes of COS neural cells will be characterized across a panel of existing and validated assays. Third, mRNA and microRNA expression of COS neural cells will be integrated through causal network interference analysis in order to identify key microRNA regulators. Finally, we will begin mechanistic studies of candidate microRNAs altered in COS. We hope to use our novel hiPSC based platform to identify molecular insights into COS which may be generalizable across SCZD.

Public Health Relevance

The goal of this application is to model the early events that contribute to the onset of schizophrenia by reprogramming skin samples from patients with childhood onset schizophrenia (COS) into human induced pluripotent stem cells (hiPSCs). By differentiating these COS hiPSCs into neural progenitor cells (NPCs) and neurons, we will identify specific cellular phenotypes and expression changes associated with COS neural cells in vitro. We hope to find insights into the mechanism of disease initiation and progression in schizophrenia, in order to one day reverse the disrupted molecular pathways that contribute to this debilitating disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH101454-02
Application #
8729399
Study Section
Special Emphasis Panel (ZMH1)
Program Officer
Panchision, David M
Project Start
2013-09-01
Project End
2018-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10029
Ho, Seok-Man; Hartley, Brigham J; Tcw, Julia et al. (2016) Rapid Ngn2-induction of excitatory neurons from hiPSC-derived neural progenitor cells. Methods 101:113-24
Hartley, Brigham J; Brennand, Kristen J (2016) Neural organoids for disease phenotyping, drug screening and developmental biology studies. Neurochem Int :
Fromer, Menachem; Roussos, Panos; Sieberts, Solveig K et al. (2016) Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nat Neurosci 19:1442-1453
Topol, Aaron; Zhu, Shijia; Hartley, Brigham J et al. (2016) Dysregulation of miRNA-9 in a Subset of Schizophrenia Patient-Derived Neural Progenitor Cells. Cell Rep 15:1024-36
Kocerha, J; Dwivedi, Y; Brennand, K J (2015) Noncoding RNAs and neurobehavioral mechanisms in psychiatric disease. Mol Psychiatry 20:677-84
Hartley, B J; Tran, N; Ladran, I et al. (2015) Dopaminergic differentiation of schizophrenia hiPSCs. Mol Psychiatry 20:549-50
Lee, Inkyu S; Carvalho, Claudia M B; Douvaras, Panagiotis et al. (2015) Characterization of molecular and cellular phenotypes associated with a heterozygous CNTNAP2 deletion using patient-derived hiPSC neural cells. NPJ Schizophr 1:
Brennand, K; Savas, J N; Kim, Y et al. (2015) Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. Mol Psychiatry 20:361-8
Ho, Seok-Man; Topol, Aaron; Brennand, Kristen J (2015) From ""directed differentiation"" to ""neuronal induction"": modeling neuropsychiatric disease. Biomark Insights 10:31-41
Mertens, Jerome; Wang, Qiu-Wen; Kim, Yongsung et al. (2015) Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature 527:95-9

Showing the most recent 10 out of 20 publications