Molecular basis of disease-associated differentiation dysfunction in single cells

Funding Type: 
Basic Biology V
Grant Number: 
ICOC Funds Committed: 
Public Abstract: 

Despite years of research, little is known about the molecular mechanisms that contribute to neurodevelopmental disorders such as autism, and currently there are few therapeutic options. To understand such diseases and develop successful therapies, we need for accurate disease models. Culture of disease-relevant cell types offers the opportunity to investigate aspects of the disease that are impossible to study in people or mouse models. Differentiation of human pluripotent stem cells has been shown to recapitulate many aspects of human development, including the molecular cues required for brain development. We have generated iPSCs (induced pluripotent stem cells) from several patients clinically diagnosed with Fragile X Syndrome, a leading genetic cause of autism. Our Fragile X-iPSC lines exhibit aberrant neurogenesis, a phenotype consistent with other neurodevelopmental disorders. We propose to correct the disease-causing mutations in our patient stem cell lines, thereby generating genetically matched control cell lines. Using state of the art global genome and gene expression profiling techniques, we will build a molecular model of the events that occur during neural differentiation of Fragile X-iPSCs. Results of these studies will provide a detailed understanding of the molecular events underlying neurodevelopmental disorders, identify dysfunctional genes/pathways in Fragile X Syndrome, and identify molecular targets with therapeutic potential.

Statement of Benefit to California: 

The incidence of autism and autism spectrum disorders cases diagnosed in California and worldwide has increased dramatically in recent years. The molecular mechanisms that contribute to neurodevelopmental disorders such as autism remain elusive, and currently there are no therapeutic treatments for autism. We propose to use patient-specific induced pluripotent stem cells and state of the art genetic analysis techniques to build a molecular map of Fragile X Syndrome, the most common form of inherited autism. Results of our study will benefit the citizens of California by increasing our knowledge about the mechanisms underlying neurodevelopmental disorders and identifying molecular targets with therapeutic potential.