Callie Kwartler

Moyamoya disease (MMD), characterized by bilateral progressive stenosis and occlusion of the internal carotid arteries, is a common cause of stroke in children. Currently, the only treatment for MMD patients is surgical correction, and the disease causes high morbidity and mortality. Although multiple genetic factors predisposing to MMD have been identified, there is no consensus about a common mechanism of disease pathogenesis. Pathology from the affected vessels suggests that smooth muscle cell (SMC) proliferation and migration may be an important driver of the disease. Of the known genes for MMD, many encode proteins involved in chromatin remodeling. Our data so far supports they hypothesis that dysregulation of chromatin remodeling prevents SMCs from fully differentiating and that the lack of differentiation causes excessive proliferation, migration, and reliance on glycolysis for energy, thus underlying MMD pathogenesis. We are a molecular biology lab that uses mouse models and induced pluripotent stem cell models to investigate this hypothesis. Current projects focus on: - The role of nuclear actin in SMC development – includes single cell transcriptomics and epigenomics on mouse embryos and cultured cells to identify specific pathways affected by nuclear actin - The INO80 chromatin remodeling complex in SMC development – includes biochemical assays to characterize complex function and ChIP assays to identify complex localization - Glycolytic metabolism as a common phenotype among MMD patients that can be exploited therapeutically – includes generating new MMD stem cell lines by reprogramming patient cells or by Crispr/Cas9 editing and using a Seahorse analyzer to assess real-time cell metabolism