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.
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.
|Grochowski, Christopher M; Gu, Shen; Yuan, Bo et al. (2018) Marker chromosome genomic structure and temporal origin implicate a chromoanasynthesis event in a family with pleiotropic psychiatric phenotypes. Hum Mutat 39:939-946|
|Hoffman, Gabriel E; Schrode, Nadine; Flaherty, Erin et al. (2018) New considerations for hiPSC-based models of neuropsychiatric disorders. Mol Psychiatry :|
|Readhead, Benjamin; Hartley, Brigham J; Eastwood, Brian J et al. (2018) Expression-based drug screening of neural progenitor cells from individuals with schizophrenia. Nat Commun 9:4412|
|Mitchell, A C; Javidfar, B; Pothula, V et al. (2018) MEF2C transcription factor is associated with the genetic and epigenetic risk architecture of schizophrenia and improves cognition in mice. Mol Psychiatry 23:123-132|
|Xu, J; Hartley, B J; Kurup, P et al. (2018) Inhibition of STEP61 ameliorates deficits in mouse and hiPSC-based schizophrenia models. Mol Psychiatry 23:271-281|
|Guennewig, Boris; Bitar, Maina; Obiorah, Ifeanyi et al. (2018) THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry 8:89|
|Li, Zeran; Del-Aguila, Jorge L; Dube, Umber et al. (2018) Genetic variants associated with Alzheimer's disease confer different cerebral cortex cell-type population structure. Genome Med 10:43|
|Hoffman, Gabriel E; Hartley, Brigham J; Flaherty, Erin et al. (2017) Transcriptional signatures of schizophrenia in hiPSC-derived NPCs and neurons are concordant with post-mortem adult brains. Nat Commun 8:2225|
|Brennand, Kristen J (2017) Personalized medicine in a dish: the growing possibility of neuropsychiatric disease drug discovery tailored to patient genetic variants using stem cells. Stem Cell Investig 4:91|
|Powell, S K; Gregory, J; Akbarian, S et al. (2017) Application of CRISPR/Cas9 to the study of brain development and neuropsychiatric disease. Mol Cell Neurosci 82:157-166|
Showing the most recent 10 out of 46 publications