Anders Malmström, professor, group leader
Phone: +46 46 222 70 57
The aim of our research is to increase the understanding of composition and function of proteoglycans in extracelllar matrix and how a tissue of this type is remodeled during normal and patophysiological conditions. Specifically we aim to elucidate the biosynthetic mechanisms for generation of the complex copolymeric structure of dermatan sulfate and how this is regulated.
The experimental work is concentrated on the recently cloned chondroitin glucuronate C5-epimerase involved in the biosynthesis of dermatan sulfate. The gene regulation of the enzyme is studied as well as its organization with other enzymes. such as the sulfotransferases, involved in the biosynthesis to clarify how the complex dermatan sulfate structure is accomplished. Targeting of the gene in mouse and the frog Xenopus laevis indicate that the enzyme is required for guidance of neural crest cells and for organization of collagen fibers. Further investigations are performed in these two systems. The epimerase ins highly expressed in squamous cell carcinoma why its potential effect on tumor progression is investigated.
To understand the function of dermatan sulfate proteoglycans we study remodeling in animals and in humans. In humans we study the remodeling of normal and preterm cervical ripening to define regulatory principles in cervix and uterus to generate a permissive cervix and a contractile uterus. The intracellular signaling pathways from defined heparan and dermatan sulfate motifs to gene expression and contractility are being explored.
Data suggest that dermatan sulfate has functions in regulation of cell proliferation, remodeling of extracellular matrix and recruitment of white blood cells and fibroblasts. The disturbed cervical ripening related to both preterm birth and high frequency instrumental deliveries and ensuing neonatal complications is of importance to control. We have identified polysaccharides with decrease delivery time by increasing contractility of uterus and ripening of the cervix. This drug is currently in a phase II study for treatment of protracted labor.