Chemical Cell Surface Engineering

University Of California Berkeley, Berkeley CA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): 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.