HCS 2021 Webinar Series

Epigenetic control of vascular homeostasis and smooth muscle function

Unlike cardiac and skeletal myocytes, differentiated vascular smooth muscle cells present the remarkable property of dynamically change their phenotypes and functions in response to physiological and pathological modifications of their microenvironment. For example, we have recently demonstrated that vascular smooth muscle cells downregulate their lineage-specific functions to transition into multiple disease-protecting or promoting states in atherosclerosis and coronary artery disease. This marked plasticity involves a tight yet dynamic transcriptional and epigenetic regulation of the smooth muscle cell gene repertoire. My laboratory is primarily interested in investigating epigenetic mechanisms controlling vascular smooth muscle cell phenotypic state. In this presentation, we will focus on the discovery of a central epigenetic axis, including chromatin and DNA modifications, regulating smooth muscle cell lineage identity and vascular homeostasis, and its possible impact in major chronic cardiovascular diseases.  

The Role of Myosin Vb in Maintaining Epithelial Polarity and Homeostasis

Myosin Vb is a molecular motor that is highly expressed in epithelial cells. Inactivating mutations in Myosin Vb causes Microvillus Inclusion Disease, a rare disorder characterized by severe, unremitting diarrhea. Mutations in Myosin Vb are also linked with intrahepatic cholestasis. My work seeks to elucidate the role of Myosin Vb in health and disease. Using mouse models, an engineered swine model of MVID, human tissue and intestinal organoids, my work has demonstrated that dysfunctional Myosin Vb results in a loss of apical sodium transporters (NHE3 and SGLT1) in the intestine. The small intestine is the major site of water absorption, driven by sodium transport. Mislocalization of sodium transporters resulting from loss of Myosin Vb thus causes malabsorptive diarrhea. Additionally, my work has demonstrated that the cystic fibrosis transmembrane conductance regulator (CFTR) is functional in Myosin Vb deficient mice. This results in CFTR mediated chloride secretion that further exacerbates diarrhea and dehydration by promoting water loss from the intestine. In a swine model of MVID, liver aberrations were observed in the bile canaliculi, supporting data suggesting that mutations in Myosin Vb contribute to cholestasis. Collectively, my research demonstrates that Myosin Vb is an important regulator of apical transporters in the intestine and liver. This work has the potential to provide novel targets for the development of specialized therapeutics to treat diarrhea and cholestasis. 

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