Array development of anti-inflammatory peptoid-graft polymers for islet delivery

Summary

Principal Investigator: Matthew Webber
Abstract: DESCRIPTION (provided by applicant): 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 [unreadable]-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.
Funding Period: 2013-09-01 - 2016-08-31
more information: NIH RePORT

Detail Information

Research Grants30

  1. A TOLERANCE APPROACH TO XENOTRANSPLANTATION
    David H Sachs; Fiscal Year: 2013
    ..abstract_text> ..
  2. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  3. Antigen Loaded Particles for Tolerance Induction
    Lonnie D Shea; Fiscal Year: 2013
    ....
  4. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  5. Ex Vivo Tolerance for Xenotransplantation of Diabetes P2
    Camillo Ricordi; Fiscal Year: 2013
    ..Furthermore, this proposal transforms the program from one based on the founder to a multi-institutional partnership, including the University of Miami-Diabetes Research Institute with their wealth of knowledge and facilities. ..
  6. MOLECULAR BASIS OF CHOLESTEROL METABOLISM
    Joseph L Goldstein; Fiscal Year: 2013
    ..Such an integrated interdisciplinary approach is possible only through continued support of this PPG. ..
  7. Immunomodulatory and regenerative effects of mesenchymal stem cells on allografts
    Norma S Kenyon; Fiscal Year: 2013
    ..Furthermore, MSC administration may constitute a safe and effective way to reverse rejection episodes. ..
  8. Molecular Analyses and Interventions for Biodefense and Emerging Pathogens
    Olaf Schneewind; Fiscal Year: 2013
    ..Research and training at the GLRCE is governed by a mechanism involving ongoing review of scientific excellence and translational goals, inter-institutional advisory boards and external scientific advisory bodies. ..
  9. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
    ..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..
  10. Improving Cardiac Function After Myocardial Infarction
    Steven R Houser; Fiscal Year: 2013
    ..A gene vector core will generate AAV6 vectors with novel therapeutics for testing in the pig Ml model. An administrative core will ensure data sharing and effective use of all resources. ..