The PI is an MD/D.Phil who has completed clinical training and is committed to a career in academic research. This proposal describes a 5 year training program designed to establish the PI as an independent researcher at the interface between matrix biology and immunology. This program is focused on the role of the extracellular matrix (ECM) in the regulation of adaptive immune responses. Specifically the PI proposes to investigate the contribution of hyaluronan (HA), a prominent component of inflammation, to CD4+CD25+ regulatory T-cell (TR ) function. Recent work (Bollyky et. al., in review) demonstrates that intact high-molecular weight HA (HMW-HA) promotes TR mediated suppression while low-molecular weight HA, generated during injury and infection, does not. These effects are mediated by CD44. Furthermore high concentrations of HMW-HA directly inhibit lymphocyte proliferation. Preliminary data support a similar dynamic in mice. It is proposed that the local state of HA provides contextual cues to TR, thereby linking the regulation of adaptive immune responses to the inflammatory milieu. Building on these observations the PI proposes to: 1) Characterize the effects of HA size on human TR suppressor function and number. 2) Recapitulate the HA-TR model in mice. 3) Determine the signaling events which mediate differential effects of HA based on its size. 4). Develop animal models to explore the therapeutic potential of HA and other ECM components in transplantation and autoimmunity. The resources and expertise available to the PI are uniquely suited to this project. Dr. Gerald Nepom, the primary mentor to the PI, is a prominent immunologist with extensive experience in autoimmunity. Other collaborators include Dr. Tom Wight, an international authority on HA, and Dr. Robert Vernon, a bioengineer who has developed a model system for pancreatic islet transplantation in rodents. This will facilitate the evaluation of ECM components in tolerance induction both in vitro and in vivo. This collaboration presents an ideal opportunity for consilience between immunology and matrix biology. The relevance of this project to public health lies in the potential to prevent autoimmunity and transplant rejection via manipulation of the ECM. In this proposal these findings are applied to the development of an animal model for transplantation in diabetes.
