The Generation and Characterization of Autism iPSCs
Deptartment of Neurology & Cell Biology, Rutgers University
Autism is a uniquely human disorder that affects language, emotional reciprocity and motor and cognitive behaviors. The disorder is complex genetically, and the clinical symptoms are heterogeneous with each individual phenotypically distinct. Moreover autism affects how the brain develops and functions both before and after birth.
Because neurons cannot be obtained from humans, the identification of developmental and neurobiological defects in autism is difficult, yet essential if new therapies to treat or prevent the disorder are to be developed. Importantly, recent advances in stem cell research now make the identification of developmental and molecular defects in autism possible. Significantly for our studies, scientists have identified the genes that are sufficient to produce stem cells. These genes can be efficiently introduced into cells obtained from people, like blood cells, and transform them into stem cells. These cells have the potential to generate all the cells of the embryo, and are called induced pluripotent stem cells (iPSCs). Moreover, one can now add developmentally relevant growth factors to the iPSCs in culture and promote their maturation into different cell types including neurons. Thus iPSCs provide a new experimental system to study human specific diseases. Because autism affects brain development, iPSCs present a unique opportunity for studying the cellular and molecular basis of the disorder: allowing us to examine every stage a cell undergoes as it transitions from embryonic stem cell into mature brain neuron.
We plan to differentiate iPSCs into neurons to determine what developmental pathways are affected in individuals with autism. The goal of this study is to generate and characterize autism and control iPS cell lines. These lines will be derived from individuals living in NJ, who are already participating in a NJ ACE funded research project on the genetic basis of autism. These individuals have been carefully diagnosed and have been selected because family members also display a specific language disorder. By focusing on this subgroup the complexities of the disorder are likely to be reduced. In addition, controls for each autism iPS cell line will be unaffected siblings as opposed to a completely unrelated individual that is typically used in such studies. Both study designs will likely make the identification of genetic, developmental, and molecular defects easier. We will then characterize these lines by differentiating them into different types of neurons. We will investigate whether autism causes differences in their proliferation, differentiation, synaptic development, as well as neuronal physiology and signaling. Molecular analysis will identify the gene expression differences associated with the above developmental defects. Finally FDA-approved drugs will be screened for rescuing effects. Upon the completion of these studies we will determine the cell biological, molecular and genetic basis (i.e the biological signature) of ASD-affected individuals living in NJ. This information will undoubtedly lead to a detailed understanding of the neurobiological defects associated with ASD in these individuals. At the end of the proposal we will have hopefully identified FDA-approved drugs that can partially or completely reverse the disease phenotypes in iPSCs and will be well placed to test these and related drugs in individuals with autism.