The role of glycosylation in cell-state transitions during development and disease

University Of Mississippi, University MS

Investigators

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Abstract

Project Summary Cell-state transitions involve the coordinated transformation of cellular identity, physiology, and morphology. These cellular processes occur at pivotal points in cardiac development and in the pathogenesis of cardiac disease. Glycans have a vital role in cardiac development as revealed by the high percentage of cardiac malformations found in patients with congenital glycosylation defects. Here we propose to investigate the role of glycans in the cell state transitions that occur during cardiac development and during cardiac disease. Glycans have been shown to be involved in cell-state transitions such as epithelial-to-mesenchymal transitions (EMT) and the differentiation of cells from a stem cell state to a differentiated state. Our preliminary single-cell mRNA sequencing (scRNAseq) analysis has identified three cell state transitions during the early stages of heart tube development: EMT, mesenchymal-to-epithelial transition (MET), and myocardial differentiation. Disease specific cell-state transitions including fibrosis and de-differentiation have been also identified in hyperglycemia-mediated heart disease. During our pilot project, we developed a zebrafish fetal hyperglycemia disease model and discovered that sialic acid enrichment in the outflow tract and ventricle of the heart is lost in hyperglycemic- hearts. Due to the high molecular conservation and wide array of genetic and imaging tools, zebrafish is an excellent model system in which to investigate the role of glycans in cardiac development and disease. To investigate the role of glycans in cardiac cell state transitions we propose to: 1) Determine the role of the O- linked glycan present in the oncofetal isoform of the extracellular matrix glycoprotein fibronectin (Fn1) during normal and hyperglycemic mediated cell-state transitions, 2) Determine how changes to the cardiomyocyte glycocalyx regulate normal and hyperglycemic-mediated myocardial cell-state transitions, and 3) Investigate the role of O-linked -N-actylglucoasamine (O-GlcNAC) in fetal hyperglycemia-mediated cardiac malformations. These aims will open new research avenues for my laboratory, investigating the role of glycans in cardiac development both at the level of a single-glycan (aim 1, 3) and collectively at the level of the glycocalyx (aim 2). Since both glycoscience and metabolism-related diseases are new fields for my laboratory we have created a mentoring committee with experts (Dr. Paszek and Dr. Gibert) in each of these fields, respectively. We expect these studies to yield preliminary data that will lay the groundwork for successful R01-level external funding and ultimately the identification of fundamental principles underlying cardiac development and the pathogenesis of fetal hyperglycemic-related heart defects.