Using animal models and high throughput immunoprecipitation assays to characterize disease subtypes and mechanisms of action of autism
It is increasingly acknowledged that autism is in fact not one disease with a single set of defined symptoms, but rather can appear as a spectrum of disorders with an array of possible causes, many of which are genetically linked. Understanding the complex genetic pathways and protein interactions linked to autism spectrum disorders (ASD) is a critical step towards characterizing different variants and ultimately developing effective treatment options.
Dr. Stephen E.P. Smith
Dr. Smith’s scientific career focuses on answering the underlying questions that explain the root causes and ongoing morbidities of autism. Dr. Smith has developed some of the earliest model organisms for studying autism including a Maternal Immune Activation (MIA) mouse model and a UBE3A overexpressing mouse. While animal models are essential for observing the effects of genetically linked autism in vivo, in order to truly understand the underlying mechanisms of autism, Dr. Smith had to develop a new system capable of capturing protein-protein interactions. This technology is called quantitative multiplex immunoprecipitation and it maps out how proteins interact with each other. Dr. Smith’s group is using this system to pinpoint how different mutations affect the protein machinery at the glutamate synapse, which is where the brain processes and stores information.
Immunoprecipitation measured by flow cytometry (IP-FCM) is a microbead-based assay that allows rapid, quantitative measurements of both absolute protein levels and protein-protein interactions. Dr. Smith’s group has developed a 20-plex array capable of assaying over 400 protein-protein interactions overnight. Dr. Smith uses this multiplex IP-FCM system to measure the state of signal transduction networks following neuronal activity, agonist/antagonist stimulation, or responses to genetic mutations associated with autism.
A novel area that Dr. Smith is working on now is the development of immuno-affinity purification of synaptosomes. Synaptosomal fractionation techniques are effective at enrichment but not purification, and the new technique Dr. Smith is developing will allow better specificity to select synaptosome subtypes.
Dr. Smith is interested in using his background in animal model development and high throughput IP-FCM methods to collaborate towards improving disease characterization techniques and treatment options for patients with autism.
Stage of Development
- Pre-clinical in vitro
- Pre-clinical in vivo
- Collaborative research opportunity
- Development opportunity
- Sponsored research agreement
- Consultation agreement
- Smith S, Neier S, Reed B et al. Multiplex matrix network analysis of protein complexes in the human TCR signalosome. Science Signaling. 2016;9(439):rs7-rs7.
- Southwell A, Smith S, Davis T et al. Ultrasensitive measurement of huntingtin protein in cerebrospinal fluid demonstrates increase with Huntington disease stage and decrease following brain huntingtin suppression. Sci Rep. 2015;5:12166.
- Smith S, Bida A, Davis T et al. IP-FCM measures physiologic protein-protein interactions modulated by signal transduction and small-molecule drug inhibition. PLoS ONE. 2012;7(9):e45722.
- Smith S, Zhou Y, Zhang G, Jin Z, Stoppel D, Anderson M. Increased gene dosage of Ube3a results in autism traits and decreased glutamate synaptic transmission in mice. Science Translational Medicine. 2011;3(103):103ra97-103ra97.
- Smith S, Li J, Garbett K, Mirnics K, Patterson P. Maternal immune activation alters fetal brain development through interleukin-6. Journal of Neuroscience. 2007;27(40):10695-10702.
To learn more about partnering with Seattle Children’s Research Institute on this or other projects, please contact:
Dr. Elizabeth Aylward
Director, Office of Science-Industry Partnerships