Reducing complications surrounding islet transplantation with new materials could improve current strategies to treat type 1 diabetes mellitus. To date, new strategies have focused on limiting the activation of immune cells or preventing blood-mediated inflammatory response through immunoisolation of encapsulated islets or by coating islets with materials to change surface properties. Here, we seek to develop new peptidomimetic materials for use in coating/encapsulating islets that not only inhibit the inflammatory response, but actively promote an anti-inflammatory response and promote immune tolerance to the transplant. We first outline a new array method for high-throughput screening of short peptoid sequences. Peptoids, a peptidomimetic class of molecules, have gained popularity in recent years and have potential advantages when compared to peptides that include less risk for immunogenicity and increased chemical building block diversity. New methods proposed here for the preparation and array screening of peptoids could be important to the discovery of new bioactive sequences or to evaluate the biological response to different peptoid chemistries. Here, arrays will be screened for the effects of different chemical properties on macrophage phenotype, evaluating for chemistries that simultaneously reduce inflammatory activation and promote anti-inflammatory and tolerogenic activation. While a lot is known about the effect of surface chemistry on classical inflammatory macrophage activation, little is known about its effect on this alternative activation phenotype. Arrays will also be screened for blood-contacting properties, inlcuding ability to limit serum adsorption and complement activation. These two criteria (macrophage phenotype and serum interactions) will be used to improve peptoid library design and identify promising peptoid sequences for anti-inflammatory signaling. Next, we will develop peptoid-graft polymers that present pendant peptoid sequences. The first polymer developed will be a synthetic ?-amino alcohol prepared via step-growth polymerization of diepoxides and primary amines on the peptoid. This polymeric backbone has shown limited macrophage activation, and it is hoped that addition of peptoid grafts will further improve the reaction to this polymer. The second material to be developed is peptoid-grafted alginate, a natural biopolymer that is widely used for islet encapsulation and delivery. Both classes of polymeric materials will be analyzed for an anti-inflammatory macrophage response and for protein adsorption and complement activation. In the final portion of the proposal, promising peptoid- grafted polymers identified to be anti-inflammatory will be further analyzed for their ability to coat/encapsulate porcine islets while promoting islet health and function. It is hoped that the proposed research plan will result in the generation of two new classes of anti-inflammatory polymeric materials that could be useful in future applications toward surface functionalization to improve islet transplantation and enable the use of allogeneic, or even xenogeneic, islets without requiring harmful systemic immune suppression.

Public Health Relevance

Though there have been advances in the use of islet transplantation to treat type 1 diabetes mellitus, the life- long immune suppression and limited donor availability make this feasible for only the most severe of cases. The proposed research will investigate the development of new polymeric materials that will be inherently anti- inflammatory and could have potential use as coatings for islets to preclude the need for immune suppression and expand donor availability to non-human (xenogeneic) sources. Such a strategy could greatly improve the quality of life for young patients faced with life-long disease management and compromised health as a result of diabetes.

Agency
National Institute of Health (NIH)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DK101335-02
Application #
8737733
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Castle, Arthur
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Internal Medicine/Medicine
Type
Schools of Arts and Sciences
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02142