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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK080178-05
Application #
8115204
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2007-09-30
Project End
2012-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
5
Fiscal Year
2011
Total Cost
$143,905
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Evanko, Stephen P; Potter-Perigo, Susan; Bollyky, Paul L et al. (2012) Hyaluronan and versican in the control of human T-lymphocyte adhesion and migration. Matrix Biol 31:90-100
Bollyky, Paul L; Bogdani, Marika; Bollyky, Jennifer B et al. (2012) The role of hyaluronan and the extracellular matrix in islet inflammation and immune regulation. Curr Diab Rep 12:471-80
Long, S Alice; Rieck, Mary; Tatum, Megan et al. (2011) Low-dose antigen promotes induction of FOXP3 in human CD4+ T cells. J Immunol 187:3511-20
Bollyky, Paul L; Wu, Rebecca P; Falk, Ben A et al. (2011) ECM components guide IL-10 producing regulatory T-cell (TR1) induction from effector memory T-cell precursors. Proc Natl Acad Sci U S A 108:7938-43
Bollyky, Paul L; Evanko, Stephen P; Wu, Rebecca P et al. (2010) Th1 cytokines promote T-cell binding to antigen-presenting cells via enhanced hyaluronan production and accumulation at the immune synapse. Cell Mol Immunol 7:211-20
Bollyky, Paul L; Falk, Ben A; Long, S Alice et al. (2009) CD44 costimulation promotes FoxP3+ regulatory T cell persistence and function via production of IL-2, IL-10, and TGF-beta. J Immunol 183:2232-41
Bollyky, Paul L; Falk, Ben A; Wu, Rebecca P et al. (2009) Intact extracellular matrix and the maintenance of immune tolerance: high molecular weight hyaluronan promotes persistence of induced CD4+CD25+ regulatory T cells. J Leukoc Biol 86:567-72
Bollyky, Paul L; Bice, Jeffrey B; Sweet, Ian R et al. (2009) The toll-like receptor signaling molecule Myd88 contributes to pancreatic beta-cell homeostasis in response to injury. PLoS One 4:e5063