Schizophrenia is a complex, debilitating mental health disorder associated with significant morbidity and mortality. The molecular- and cellular-based mechanisms that contribute to schizophrenia remain undefined. Although schizophrenia has classically been considered a neurotransmitter-based disorder, there is emerging evidence that dysregulation of oligodendrocyte function is a key contributor to the mental deficits seen in afflicted patients. Currently there is not a tractable system that allows for the direct interrogation of the functional properties of neural cells types from patients with schizophrenia. Patient-specific sources of cells that are capable of robust and reproducible differentiation into specific neural lineages do not exist. We propose to develop a cell-based system whereby neural cells from afflicted individuals can be functionally assayed to interrogate the molecular mechanisms underlying schizophrenia. To achieve this goal we have developed a cutting-edge proposal that that incorporates the skill and expertise of multiple disciplines.
In Aim 1 we will derive and characterize patient-specific, induced pluripotent stem (iPS) cells from juvenile-onset schizophrenia patients and controls. Since iPS cells are pluripotent, having the ability to differentiate into all cell types of the human body, in Aim 2 we will differentiate patient-specific iPS cells line into oligodendrocyte progenitor cells (OPCs) to provide a cellular source for oligodendrocytes. In the second phase of this project will characterize, compare, and functionally assay these patient-specific, iPS cell-derived oligodendrocytes from control and juvenile-onset schizophrenia patients using both in vitro and in vivo assays (Aims 3 and 4 respectively). We will also actively procure additional samples to derive and characterize patient-specific, iPS cells from juvenile-onset schizophrenia patients and controls during this second phase (Aim 5). There is great potential for patient-specific iPS cell technology to profoundly impact our understanding of human development and disease by providing genetically distinct, functional sources of human cells. By completing the aims set forth in this proposal we expect to provide a detailed characterization of oligodendrocyte function in patients afflicted with schizophrenia and provide insight into the pathophysiology of this complex disease. We have established an interdisciplinary team that combines strengths in clinical schizophrenia research, neural differentiation and function, as well as pluripotency and iPS cells to interrogate novel questions about the cellular and molecular dysfunction that contributes to schizophrenia. We expect that results from our studies will have immediate relevance to the understanding and treatment of this human disease.

Public Health Relevance

Schizophrenia is a serious psychiatric condition with a worldwide prevalence of approximately 1%. Individuals with schizophrenia experience very severe symptoms and are at an increased risk for suicide, unemployment, permanent disability, and homelessness. Affected adolescents experience even more severe symptoms, tend to be more chronically dysfunctional, suffer from greater cognitive impairments, and may have greater functional and social disability than those with adult-onset schizophrenia. Unfortunately, the cause of schizophrenia is currently unknown. Results of our studies will provide a detailed characterization of brain cell function in patients afflicted with schizophrenia and will offer insight into the mechanisms that contribute to this complex, devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
5R33MH087877-04
Application #
8327085
Study Section
Special Emphasis Panel (ZMH1-ERB-M (01))
Program Officer
Panchision, David M
Project Start
2009-09-30
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$386,388
Indirect Cost
$140,281
Name
Case Western Reserve University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Najm, Fadi J; Lager, Angela M; Zaremba, Anita et al. (2013) Transcription factor-mediated reprogramming of fibroblasts to expandable, myelinogenic oligodendrocyte progenitor cells. Nat Biotechnol 31:426-33
De Los Angeles, Alejandro; Loh, Yuin-Han; Tesar, Paul J et al. (2012) Accessing naïve human pluripotency. Curr Opin Genet Dev 22:272-82
Miller, Robert H; Tesar, Paul J (2011) Tracking down the human myelinating cell. Nat Biotechnol 29:881-3
Najm, Fadi J; Zaremba, Anita; Caprariello, Andrew V et al. (2011) Rapid and robust generation of functional oligodendrocyte progenitor cells from epiblast stem cells. Nat Methods 8:957-62
Zentner, Gabriel E; Tesar, Paul J; Scacheri, Peter C (2011) Epigenetic signatures distinguish multiple classes of enhancers with distinct cellular functions. Genome Res 21:1273-83
Najm, Fadi J; Chenoweth, Josh G; Anderson, Philip D et al. (2011) Isolation of epiblast stem cells from preimplantation mouse embryos. Cell Stem Cell 8:318-25