Asha Maria Rudjord Levann
Guest researcher, Visiting researcher
2200 København N.
Glycosaminoglycans (GAGs) are long linear polysaccharide chains of alternating disaccharide units present in the extracellular matrix, on the cell surface and intracellularly in most mammalian cells. Differences in disaccharide composition, length, glycosidic linkage and residue modifications confer a high degree of complexity and heterogeneity to different GAG motifs. Certain GAG motifs serve as scaffolds for receptor-complex formation and as reservoirs for binding of growth factors and many other small molecules. In this manner, GAGs generate morphogen gradients regulating growth factor signaling across the plasma membrane. Through these interactions, GAGs are involved in tissue formation, homeostasis, regeneration and aging. Along with this, alterations in GAG biosynthesis is associated with a number of human diseases including cancer. However, the complexity and heterogeneity of GAG chains makes them difficult to sequence and today we have limited knowledge on these specific GAG motifs and their impact on human physiology and disease.
The aim of my PhD is to genetically deconstruct and dissect the molecular functions of specific GAG motifs in human tissue. At Copenhagen Center for Glycomics we have established genetically engineered organotypic human tissue models. Employing CRISPR/Cas9 genetic engineering, I will generate a panel of primary, immortalized, human keratinocyte cell lines and tissue models with defective GAG biosynthesis. This will allow me to define structure-function relationships between specific GAG motifs and their biological functions and to dissect the impact of altered GAG biosynthesis on tissue formation and homeostasis