Dendritic epidermal T cells (DETC) reside in murine skin where they monitor epithelial cells for damage. DETC express a monoclonal gamma-delta T cell receptor (TCR) which is used to recognize an unknown antigen expressed by damaged or stressed keratinocytes. We have previously shown that DETC play roles in skin homeostasis and wound repair via the production of insulin-like growth factor-1 (IGF-1) and keratinocyte growth factors (KGFs). Work in diabetic mice and humans indicate that diminished levels of IGF-1 and KGFs at the wound site contribute to impaired wound repair. We hypothesize that impaired growth factor production and defective proliferation of keratinocytes in the diabetic wound are the result of DETC dysfunction. Initially we will determine whether DETC are functional in diabetic wounds by examining DETC activation, proliferation, and growth factor production. In addition we will investigate which mechanisms may contribute to DETC dysfunction in diabetes including: changes in insulin receptor (IR) signaling, inhibition by glucocorticoids, and decreased IGF-1 receptor (IGF-1 R) signaling. By developing an understanding of DETC-keratinocyte cross-talk during wound healing in diabetic mice we may uncover new mechanisms that can be exploited to increase the efficiency of wound repair and provide insight into the timing of IR and IGF-1 R signaling. The proposed experiments are exploratory in nature and involve type I and type II diabetic mouse models of wound repair. Diabetic non-healing wounds are a debilitating complication and treatment is a considerable burden to health services. Results from this proposal may lead to new directions aimed at targeting DETC for future therapies and studying intra-epithelial gamma-delta T cells in other tissues affected by diabetes such as the gut.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DK073098-02
Application #
7140624
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Jones, Teresa L Z
Project Start
2005-09-30
Project End
2008-08-31
Budget Start
2006-09-01
Budget End
2008-08-31
Support Year
2
Fiscal Year
2006
Total Cost
$272,297
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Taylor, Kristen R; Costanzo, Anne E; Jameson, Julie M (2011) Dysfunctional ýýýý T cells contribute to impaired keratinocyte homeostasis in mouse models of obesity. J Invest Dermatol 131:2409-18
Taylor, Kristen R; Mills, Robyn E; Costanzo, Anne E et al. (2010) Gammadelta T cells are reduced and rendered unresponsive by hyperglycemia and chronic TNFalpha in mouse models of obesity and metabolic disease. PLoS One 5:e11422
Mills, Robyn E; Taylor, Kristen R; Podshivalova, Katie et al. (2008) Defects in skin gamma delta T cell function contribute to delayed wound repair in rapamycin-treated mice. J Immunol 181:3974-83
Jameson, Julie; Havran, Wendy L (2007) Skin gammadelta T-cell functions in homeostasis and wound healing. Immunol Rev 215:114-22