Glycans attached to cell surface proteins and lipids mediate interactions with receptors on other cells, in the extracellular matrix, or within the same cell membrane. Collectively, cell-surface glycans constitute a glycocalyx with bulk physical properties that can also influence extracellular interactions. The biological functions of natural glycoconjugates are difficult to study due to a dearth of experimental tools. Unlike proteins and nucleic acids, glycan structures are impossible to alter with molecular precision using biological methods. The broad objective of this project is to develop chemical approaches that enable fundamental studies of cell surface glycobiology. In the last granting period, we designed synthetic glycopolymers that emulate the structures of mucin glycodomains and can be anchored to cell membranes through a lipid tail. We demonstrated that these fully synthetic materials, whose structures can be modulated with precision, can be introduced onto live cells where they acquire biological activity. In collaborative work with Prof. Valerie Weaver (UCSF) we used the glycopolymers as models of MUC1, a cell-surface mucin that is overexpressed on many cancers. Mammary epithelial cells remodeled with the glycopolymers underwent changes in integrin clustering and extracellular matrix binding that were similar to the effects of MUC1 overexpression. These results validated synthetic glycopolymers as functionally relevant tools for unraveling the biology of the cancer glycocalyx. In the next granting period, we will build upon our work with synthetic glycopolymers with three Specific Aims.
In Aim 1, we will build a collection of glycopolymers possessing varied glycan structures, more biologically authentic backbones, and tunable plasma membrane residence times.
In Aim 2, we will continue our collaborative work with Prof. Weaver's group, using the glycopolymers from Aim 1 to ascertain the roles of mucin glycodomains in regulating cell adhesion, survival and proliferation in vitro, and metastasis in vivo.
In Aim 3 we will use glycopolymers to probe the involvement of SigLecs in NK cell-mediated transplant rejection; we also seek to develop immunoprotective materials for islet cell transplants based on our findings.
All human cells are coated with complex sugar molecules, also called glycans, whose functions are not well understood. It is known, however, that glycans change when cells become cancerous, and that cell-surface sugars can affect the way our immune system reacts to foreign cells such as those from an organ transplant. This project seeks to develop technologies rooted in chemistry that can be used to better understand how sugars contribute to cancer and to the immune response against transplanted cells and, in the long-term, this work will help us identify new avenues for cancer therapy and for preventing transplant rejection.
|Barnes, J Matthew; Przybyla, Laralynne; Weaver, Valerie M (2017) Tissue mechanics regulate brain development, homeostasis and disease. J Cell Sci 130:71-82|
|Freeman, Spencer A; Goyette, Jesse; Furuya, Wendy et al. (2016) Integrins Form an Expanding Diffusional Barrier that Coordinates Phagocytosis. Cell 164:128-140|
|Bhat, Ramray; Belardi, Brian; Mori, Hidetoshi et al. (2016) Nuclear repartitioning of galectin-1 by an extracellular glycan switch regulates mammary morphogenesis. Proc Natl Acad Sci U S A 113:E4820-7|
|Hudak, Jason E; Belardi, Brian; Appel, Mason J et al. (2016) Piperidine-based glycodendrons as protein N-glycan prosthetics. Bioorg Med Chem 24:4791-4800|
|Kai, FuiBoon; Laklai, Hanane; Weaver, Valerie M (2016) Force Matters: Biomechanical Regulation of Cell Invasion and Migration in Disease. Trends Cell Biol 26:486-497|
|Xiao, Han; Woods, Elliot C; Vukojicic, Petar et al. (2016) Precision glycocalyx editing as a strategy for cancer immunotherapy. Proc Natl Acad Sci U S A 113:10304-9|
|Agarwal, Paresh; Beahm, Brendan J; Shieh, Peyton et al. (2015) Systemic Fluorescence Imaging of Zebrafish Glycans with Bioorthogonal Chemistry. Angew Chem Int Ed Engl 54:11504-10|
|Agarwal, Paresh; Bertozzi, Carolyn R (2015) Site-specific antibody-drug conjugates: the nexus of bioorthogonal chemistry, protein engineering, and drug development. Bioconjug Chem 26:176-92|
|Woods, Elliot C; Yee, Nathan A; Shen, Jeff et al. (2015) Glycocalyx Engineering with a Recycling Glycopolymer that Increases Cell Survival In Vivo. Angew Chem Int Ed Engl 54:15782-8|
|Kramer, Jessica R; Onoa, Bibiana; Bustamante, Carlos et al. (2015) Chemically tunable mucin chimeras assembled on living cells. Proc Natl Acad Sci U S A 112:12574-9|
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