Gamma Delta T cell and keratinocyte cross-talk in diabetic wounds

描述（由申请人提供）：树突状表皮T细胞（DETC）存在于小鼠皮肤中，监测上皮细胞的损伤。DETC表达单克隆γ - δ T细胞受体（TCR），用于识别受损或应激角质形成细胞表达的未知抗原。我们之前已经证明DETC通过产生胰岛素样生长因子-1 （IGF-1）和角质细胞生长因子（kgf）在皮肤稳态和伤口修复中发挥作用。对糖尿病小鼠和人类的研究表明，伤口部位IGF-1和KGFs水平的降低有助于伤口修复受损。我们假设糖尿病伤口中生长因子产生受损和角化细胞增殖缺陷是DETC功能障碍的结果。首先，我们将通过检测DETC的激活、增殖和生长因子的产生来确定DETC是否在糖尿病伤口中起作用。此外，我们将研究糖尿病DETC功能障碍的机制，包括胰岛素受体（IR）信号的改变、糖皮质激素的抑制和IGF-1受体（igf - 1r）信号的减少。通过对糖尿病小鼠伤口愈合过程中detc -角化细胞串话的理解，我们可能会发现新的机制，可以用来提高伤口修复的效率，并提供对IR和igf - 1r信号传导时间的见解。我们提出的实验是探索性的，涉及I型和II型糖尿病小鼠伤口修复模型。糖尿病无法愈合的伤口是一种使人衰弱的并发症，治疗对卫生服务造成相当大的负担。这一建议的结果可能会为未来的治疗提供新的方向，旨在针对DETC，并研究受糖尿病影响的其他组织（如肠道）中的上皮内γ - δ T细胞。

DESCRIPTION (provided by applicant): 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.