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 #
1R01MH101454-01
Application #
8573459
Study Section
Special Emphasis Panel (ZMH1-ERB-L (04))
Program Officer
Panchision, David M
Project Start
2013-09-01
Project End
2018-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$432,191
Indirect Cost
$177,211
Name
Icahn School of Medicine at Mount Sinai
Department
Psychiatry
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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
Hook, Vivian; Brennand, Kristen J; Kim, Yongsung et al. (2014) Human iPSC neurons display activity-dependent neurotransmitter secretion: aberrant catecholamine levels in schizophrenia neurons. Stem Cell Reports 3:531-8
Hashimoto-Torii, Kazue; Torii, Masaaki; Fujimoto, Mitsuaki et al. (2014) Roles of heat shock factor 1 in neuronal response to fetal environmental risks and its relevance to brain disorders. Neuron 82:560-72
Brennand, Kristen J; Landek-Salgado, Melissa A; Sawa, Akira (2014) Modeling heterogeneous patients with a clinical diagnosis of schizophrenia with induced pluripotent stem cells. Biol Psychiatry 75:936-44