Fucosylated glycans are involved in a variety of physiological and pathological processes in eukaryotic organisms including angiogenesis, fertilization, embryogenesis, cell adhesion, inflammation, and tumor metastasis. Some major gaps in our knowledge of fucosylated glycans include how they are dynamically regulated during embryo development and cancer progression, and their specific cellular functions. The broad objective of this project is to develop chemical tools to advance our understanding of the biological functions of fucosylated glycans in these processes. In the last granting period, we designed chemoenzymatic methods to synthesize guanidine 5?- diphosphate-?-L-fucose, the universal fucosyl donor, and chemically defined fucosides, as well as their structurally related derivatives. Using these chemical tools, we developed a few platforms to study the biological functions of fucosylated glycans both in vitro and in vivo, including a microarray platform to perform structure-activity relationship analysis of fucosides with fucose-binding proteins. In collaboration with Prof. Florence Marlow (Einstein), we developed a method to detect and image newly synthesized fucosides in zebrafish embryos using GDP-fucose functionalized with a bioorthogonal tag as the metabolic precursor. We discovered that up-regulation of N-linked fucosylation disrupts zebrafish dorsal-ventral patterning in the early embryogenesis by inhibiting the Wnt signaling pathway. Using a combination of fucosyltransferase and click chemistry, we developed a method to analysis the dynamic changes of cell-surface peripheral N- acetyllactosamine-bearing glycans in murine and human patient samples. These results validated the functional relevance of our chemoenzymatic tools for unraveling the biology of fucosylated glycans. Building upon this work, in the next granting period, we will invent new chemical tools, which will be used in conjunction with our established tools, to study the role of fucosylated glycans in the interaction between the immune system and tumors.
In Aim 1, we will study the role of fucosylated glycans from the aspect of tumor cells. Specifically, we will investigate mechanisms by which tumor cells use fucosylated glycans to suppress immune cell activation (Aim 1). In the second part of this project, we will study the role of fucosylated glycas from the aspect of the immune system. We will comprehensively characterize the changes in cell-surface fucosylation during immune cell activation (Aim 2). Finally, we will design a method to engineer fucosylated glycans in immune cells and evaluate their anti-tumor activities (Aim 3). The chemical biology tools developed in this project will be made accessible to non-specialists for studying the biological functions of fucosides or the related glycans in their own systems.
Given that aberrant fucosylation is linked to immune disorders and cancer, understanding dynamic regulations of this form of glycosylation during immune cell activation and cancer progression is essential for treating human disease. From the studies proposed in this project, we will elucidate the mechanism by which fucosylated glycans is recruited and functionally operating in above processes. Such studies will pave the way for the development of new glycan-based therapies that may be combined with other existing therapies to treat human disease such as cancer.
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|Nordstrøm, Lars Ulrik; Sironi, Juan; Aranda, Evelyn et al. (2015) Discovery of autophagy inhibitors with antiproliferative activity in lung and pancreatic cancer cells. ACS Med Chem Lett 6:134-9|
|Jiang, Hao; English, Brian P; Hazan, Rachel B et al. (2015) Tracking surface glycans on live cancer cells with single-molecule sensitivity. Angew Chem Int Ed Engl 54:1765-9|
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