Exploring the precise role of heparanase via small molecule probes

University Of Florida, Gainesville FL

Investigators

Abstract

Abstract The extracellular matrix (ECM) is an essential component of the microenvironment of cells and is known to provide mechanical supports for organs and tissues, as well as loci for cell adhesion, interaction, and signaling to regulate various cell functions. Heparan sulfate proteoglycans (HSPGs), major components in the ECM of all tissue types, maintain the structural integrity of ECM and regulate cellular signaling via binding with ECM components and protein ligands such as growth factors and chemokines. Heparanase, the only known enzyme that can cleave the heparan sulfate (HS) side chains of HSPGs and a key enzyme for ECM remodeling, regulates many cellular processes including ECM remodeling and homeostasis of cell-associated HS, and it controls the bioavailability and activity of molecules attached to HS. The importance of heparanase activity in various pathological conditions such as cancer, angiogenesis, and inflammation has been well demonstrated, however, a detailed mechanistic study of heparanase function and the precise mode of heparanase action in ECM remodeling remain elusive. Molecular probes that can dissect the different functions of heparanase can explore its precise role in ECM remodeling, however, prior to our work, there were no suitable tools for this type of investigation. Our overall research program has been built on the development of novel heparanase probes that have defined structures, and “in situ” labeling chemistry that can facilitate real-time detection of heparanase activity both in vitro and in vivo. With the support of MIRA-ESI, my lab has successfully developed efficient chemical strategies to yield novel small molecule probes to detect heparanase activity, and “in situ” labeling chemistry suitable for carbohydrate processing enzymes. In the proposed MIRA application and the long term, we will develop a library of novel heparanase probes with varying glycan substrates and use these structurally defined molecules to study the precise function of heparanase using in vitro and in vivo models involving ECM remodeling.