In mammalian organisms, nine monosaccharide building blocks are used to form cell-surface complex, higher order glycans that mediate cell-cell communication during development processes and differentiation programs. By contrast, aberrant glycosylation signals the onset of cancer. What directs pathogenic glycosylation? Is there a correlation between glycosylation patterns and cancer progression? Can we manipulate differentiation by changing the glycan coat? Despite forty years of glycobiology research, the answers to these questions remain obscure. Dynamic changes in glycosylation during many developmental processes and cancer progression are still poorly characterized. Because peripheral, higher order glycans encode information for cell-surface receptor recognition to trigger specific downstream signaling, there is an urgent and unmet need to develop methods for their detection. The long-term objective of this project is to develop chemoenzymatic methods for the specific labeling of cell-surface higher-order glycans with small-molecule biophysical probes for their characterization. To achieve this goal is to transform glycosylation enzymes into labeling reagents to target cell-surface specific glycans. Our central hypothesis is that chemoenzymatic methods for glycan detection in cells and tissue samples will have superior specificity and sensitivity than lectin- and antibody-based techniques, the current gold standard for glycan detection.
In Aim 1, we will develop chemoenzymatic methods for the labeling of four sectors of glycans on the surface of live mammalian cells and transform these methods into histological techniques to label glycans in tissue sections.
In Aim 2, we the small intestine developmental process. We will use the methods developed in Aim 1 to characterize the epithelial will use as a model system to study the role of glycans in a glycosylation patterns in this system. We will investigate the contribution of glycan-lectin interactions to the highly regulated cell migration and maturation in this compartment. Finally, we will apply the chemoenzymatic methods to screen cancer-associated glycans in lung resection samples from patients diagnosed with lung adenocarcinoma (Aim 3). Our goal is to investigate the potential role of these glycans in the evolution of lung cancer, and to pilot test their clinical utility forearly lung cancer detection.
Glycans, also known as polysaccharides, are involved in a variety of physiological and pathological processes in humans, ranging from normal to neoplastic development. Cell-surface glycans undergo drastic changes during disease progression and have great potential to be used as biomarkers for disease diagnosis. However, few methods exist to detect these glycans in live cells and tissue samples. This project is aimed to develop highly specific, sensitive, and low cost techniques to label complex glycans on the surface of live cells and apply them towards the labeling of human tumor samples in a method termed `CHoMP' (Chemoenzymatic Histology of Membrane Polysaccharides), which may be translated into a clinical diagnostic tool to guide cancer therapies.
| Briard, Jennie Grace; Jiang, Hao; Moremen, Kelley W et al. (2018) Cell-based glycan arrays for probing glycan-glycan binding protein interactions. Nat Commun 9:880 |
| Liu, Zilei; Li, Jie; Li, Suhua et al. (2018) SuFEx Click Chemistry Enabled Late-Stage Drug Functionalization. J Am Chem Soc 140:2919-2925 |
| Jiang, Hao; López-Aguilar, Aimé; Meng, Lu et al. (2018) Modulating Cell-Surface Receptor Signaling and Ion Channel Functions by In?Situ Glycan Editing. Angew Chem Int Ed Engl 57:967-971 |
| Lopez Aguilar, Aime; Meng, Lu; Hou, Xiaomeng et al. (2018) Sialyltransferase-Based Chemoenzymatic Histology for the Detection of N- and O-Glycans. Bioconjug Chem 29:1231-1239 |
| Rouhanifard, Sara H; Lopez Aguilar, Aime; Meng, Lu et al. (2018) Engineered Glycocalyx Regulates Stem Cell Proliferation in Murine Crypt Organoids. Cell Chem Biol 25:439-446.e5 |
| Ren, Gerui; Zheng, Qinheng; Wang, Hua (2017) Aryl Fluorosulfate Trapped Staudinger Reduction. Org Lett 19:1582-1585 |
| Wang, Hua; Zhou, Feng; Ren, Gerui et al. (2017) SuFEx-Based Polysulfonate Formation from Ethenesulfonyl Fluoride-Amine Adducts. Angew Chem Int Ed Engl 56:11203-11208 |
| Lopez Aguilar, Aime; Gao, Yu; Hou, Xiaomeng et al. (2017) Profiling of Protein O-GlcNAcylation in Murine CD8+ Effector- and Memory-like T Cells. ACS Chem Biol 12:3031-3038 |
| Ovryn, Ben; Li, Jie; Hong, Senlian et al. (2017) Visualizing glycans on single cells and tissues-Visualizing glycans on single cells and tissues. Curr Opin Chem Biol 39:39-45 |
| Lopez Aguilar, Aime; Briard, Jennie Grace; Yang, Linette et al. (2017) Tools for Studying Glycans: Recent Advances in Chemoenzymatic Glycan Labeling. ACS Chem Biol 12:611-621 |
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