Challenge Area: 14 --Stem Cells Challenge Topic: 14-MH-101*, """"""""Developing iPS cells for mental disorders"""""""" The recent description of somatic cell reprogramming to an embryonic stem (ES) cell-like phenotype, termed induced pluripotent stem (iPS) cell technology, presents an exciting venue toward cell-based models of disease mutations. This technology affords for the first time the potential to analyze neuronal cells grown from individuals carrying a given genetic lesion and offers a unique way of direct assessment of pathology. Recent studies have established an important role for rare copy number variants (CNVs, genomic deletions and duplications) in the etiology of schizophrenia and autism. Rare, but recurrent CNVs affecting the CNTNAP2 gene, a member of the neurexin family, have been described in both disorders. Given the high penetrance and clearly delineated genomic structure, which offers clear clues regarding the underlying functional deficit, this CNV is ideal to model at the cellular level, as well as at the level of the organism. We propose to generate iPS cells and iPS cell- derived forebrain neurons from schizophrenic patients carrying variable size CNTNAP2 gene deletions and their unaffected relatives and undertake an initial characterization of their basic morphological and electrophysiological properties. A unique aspect of our proposal is that the proposed comparisons will use as a reference point data acquired both in vitro and in vivo from hippocampal and cortical neurons from an animal model genetically engineered to carry a Cntnap2 gene deletion. Cell lines generated from individuals with schizophrenia carrying specific well-defined structural mutations offer an unprecedented opportunity to recapitulate pathologic human neural tissue formation in vitro and provide a unique platform for studies aimed at both providing valuable insights into the disease mechanisms, and the potential discovery of new compounds to treat this devastating disorder.

Public Health Relevance

There is considerable promise in generating induced pluripotent stem (iPS) cell lines from patients afflicted with central nervous system diseases, including psychiatric disorders. We propose to generate neurons from patients with schizophrenia carrying CNTNAP2 deletions, a genetic risk factor for the disease, study their properties and compare them to brain neurons of a knock/out mouse model of the same gene. This is an unprecedented opportunity for the field to combine data from human neurons carrying a bona fide genetic risk factor for schizophrenia and an established mouse model of the same genetic lesion.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
NIH Challenge Grants and Partnerships Program (RC1)
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Special Emphasis Panel (ZRG1-MDCN-A (58))
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Panchision, David M
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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