Over 1 million Americans are afflicted with type I diabetes and each year 13,000 additional children are diagnosed. Pancreatic islet cell transplantation has emerged as a promising treatment for type I diabetes, but its clinical application has been limited due to cellular immunogenicity. In nature, mucins are membrane-bound glycoproteins partially responsible for passivation of the immune response, but their size and complexity make their isolation and study difficult. The broad objective of this proposal is to engineer a cell surface coating that mimics the native mucins for the protection of islet cell in transplant therapy. This work will be accomplished through three Specific Aims: (1) Develop a modular synthesis of glycopeptide polymers;(2) evaluate the incorporation, molecular orientation, and internalization of the glycopeptide polymers;and (3) evaluate the glycopeptide polymers in the immunoisolation of pancreatic islet cells. Utilizing a modular synthetic approach a diversity of glycopeptide polymers will be synthesized and analyzed to correlate the relationship between chemical composition, macromolecular structure, and interaction of the glycopolymers with components of the innate immune system. These studies will provide a platform to enable an enhanced understanding of the immunology of complex mucin glycoproteins and provide the ability to study and perturb cellular recognition and immunogenicity with the intent to shield pancreatic islet cells from inflammation and damage during transplantation.
The research described in this application will provide a chemical approach to develop mucin mimic glycopolymers for the protection of pancreatic islet cells from eliciting an immune response during transplantation. Pancreatic islet cell transplantation has emerged as a promising therapy for the treatment of type I diabetes. The development of a modular synthetic route to mucin-like glycopolymers will permit identification of the key chemical and structural aspects responsible for biological response and permit the rational design of a mucin mimic to shield islet cells from damage and inflammation during transplantation.
|Hudak, Jason E; Canham, Stephen M; Bertozzi, Carolyn R (2014) Glycocalyx engineering reveals a Siglec-based mechanism for NK cell immunoevasion. Nat Chem Biol 10:69-75|