The research in the Sahin lab is directed at understanding the cellular mechanism(s) of axonal and synaptic development and their relationship to neurological dysfunction, especially in childhood neurological diseases. A major line of investigation in the lab is on the role of tuberous sclerosis genes (TSC1 and TSC2) in neuronal connectivity. Tuberous sclerosis (TSC) is a multi-system autosomal dominant disease, which is characterized by the formation of benign tumors (hamartomas) in several organs. The brain is almost invariably affected, and patients can present with epilepsy, autism and intellectual disability. However, a key unresolved issue is what causes the neurological symptoms in TSC patients.
We hypothesized that the miswiring of connections between neurons may contribute to the pathogenesis of neurological symptoms in TSC. Over the last few years, we have identified several steps in which TSC1/2-deficiency leads to defects in axonal specification, guidance, and myelination. More recently, our conditional deletion of Tsc1 only in cerebellar Purkinje cells provided the first evidence that disturbances in cerebellar circuitry may underlie the high prevalence of autism in patients based on autistic-like behavioral phenotypes in these animals. Finally, using diffusion tensor imaging of TSC patients, we identified deficits in white matter microstructure that parallel our findings in TSC mouse models. These discoveries will enable us to identify biomarkers that correlate with disease severity and monitor response to treatment in TSC patients. Toward that goal, we have demonstrated that mTOR inhibitors prevent myelination defects and improve neurological symptoms in the TSC mouse model, leading to mTOR inhibitor trial to improve neurocognition in TSC patients currently ongoing in our hospital. We are now using a combination of human and rodent cell culture, conditional mouse models, EEG and imaging to develop more targeted, mechanism-based treatments for TSC and related neurodevelopmental disorders.
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