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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM059907-13
Application #
8506966
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Marino, Pamela
Project Start
1999-08-01
Project End
2017-08-31
Budget Start
2013-09-20
Budget End
2014-08-31
Support Year
13
Fiscal Year
2013
Total Cost
$413,128
Indirect Cost
$89,673
Name
University of California Berkeley
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Barnes, J Matthew; Kaushik, Shelly; Bainer, Russell O et al. (2018) A tension-mediated glycocalyx-integrin feedback loop promotes mesenchymal-like glioblastoma. Nat Cell Biol 20:1203-1214
Zhou, Matthew N; Delaveris, Corleone S; Kramer, Jessica R et al. (2018) N-Carboxyanhydride Polymerization of Glycopolypeptides That Activate Antigen-Presenting Cells through Dectin-1 and Dectin-2. Angew Chem Int Ed Engl 57:3137-3142
Freeman, Spencer A; Vega, Anthony; Riedl, Magdalena et al. (2018) Transmembrane Pickets Connect Cyto- and Pericellular Skeletons Forming Barriers to Receptor Engagement. Cell 172:305-317.e10
Woods, Elliot C; Kai, FuiBoon; Barnes, J Matthew et al. (2017) A bulky glycocalyx fosters metastasis formation by promoting G1 cell cycle progression. Elife 6:
Barnes, J Matthew; Przybyla, Laralynne; Weaver, Valerie M (2017) Tissue mechanics regulate brain development, homeostasis and disease. J Cell Sci 130:71-82
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
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

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