Overview
The surfaces of cells are covered with a dense layer of glycoproteins, glycolipids, and proteoglycans, which together make up the glycocalyx. These glycoconjugates bind to growth factors, enzymes, and extracellular matrix proteins, and thereby participate in a wide variety of biological phenomena related to cell differentiation, proliferation and migration, morphogenesis, and normal and pathophysiology. To a large extent these interactions are determined by the structure of the polysaccharide chains (glycans) that distinguish the various subclasses of glycoconjugates. The assembly of these molecules involves many enzymes, substrates and cofactors and differs from the assembly of nucleic acids and proteins in not requiring a template. Understanding how cells organize the assembly process to bring about cell-type specific glycan expression and biological responses is a major problem in modern cell biology.
Research in the Esko lab utilizes a combination of chemistry, cell biology and genetics to understand the structure, assembly and function of sulfated glycosaminoglycans found on proteoglycans. The glycosaminoglycans include hyaluronan, heparan sulfate, chondroitin/dermatan sulfate, and keratan sulfate. Studies of mutant cell lines and mice bearing conditional and systemic mutations allow us to analyze glycan function in normal physiology and disease. Current work arranged by systems include:
- Proteoglycan Metabolism: We have an ongoing program to characterize mouse strains lacking specific sulfotransferases and glycosyltransferases involved in heparan and chondroitin/dermatan sulfate assembly. We are also interested in lysosomal catabolism of glycosaminoglycans and the development of methods to restore homeostasis in tissues through enzyme replacement and substrate deprivation. Part of these studies involve collaborations with companies and family foundations with interest in lysosomal storage disorders.goin
- Proteoglycans and Infectious Disease: A major effort in the lab hopes to unravel the impact of heparan sulfate and chondroitin/dermatan sulfate on bacterial sepsis. These studies involve vascular tagging to measure how the endothelial proteome and glycoproteome changes after bacterial challenge. Another set of studies focus on altering heparan sulfate in endothelial cells and myeloid cells to determine how these changes affect infection and inflammation. Another area of great interest these days concerns the role of glycosylation in SARS-CoV-2 infection.
- Proteoglycans and Cancer Biology: Projects in this area involve studies of proteoglycans in cancer cells using genome wide methods to alter glycosaminoglycan structure and function and studies of an unusual form of heparan sulfate in pancreatic adenocarcinoma. We also remain interested in multiple hereditary exostoses, a pediatric disease in which heparan sulfate deficiency results in osteochondromas.
The lab currently consists of 4 postdoc researchers, 1 graduate student, 3 technicians, and 5 undergraduates. We have lab meeting every week (Wednesdays at 10:00 am by Zoom these days), a journal club focused on Current Literature in Glycobiology (BIOM 246, Fridays at noon also by Zoom), and weekly submeetings to coordinate projects with collaborators on and off campus. Trainees receive classical training in the chemistry and biochemistry of glycans and modern training in genetics, cell biology and physiology. Until we can resume in person meetings, my Zoom portal is always open — send me an email.