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

描述(申请人提供)：树突状表皮T细胞(DETC)存在于小鼠皮肤中，它们在那里监测上皮细胞的损害。DETC表达一种用于识别受损或应激角质形成细胞表达的未知抗原的单克隆伽马-德尔塔T细胞受体(TCR)。我们之前已经证明，DETC通过产生胰岛素样生长因子-1(IGF-1)和角质形成细胞生长因子(KGFS)在皮肤动态平衡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的受损。我们推测糖尿病创面角质形成细胞的生长因子分泌受损和增殖障碍是DETC功能障碍的结果。最初，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在糖尿病创面中是否起作用。此外，我们还将探讨哪些机制可能导致糖尿病患者的DETC功能障碍，包括：胰岛素受体(IR)信号的改变，糖皮质激素的抑制，以及IGF-1受体(IGF-1R)信号的减少。通过了解糖尿病小鼠伤口愈合过程中DETC-角质形成细胞的相互作用，我们可能会发现新的机制，可以用来提高伤口修复的效率，并为IR和IGF-1R信号的时机提供洞察力。拟议的实验是探索性的，涉及I型和II型糖尿病小鼠的伤口修复模型。糖尿病无法愈合的伤口是一种使人虚弱的并发症，治疗对卫生服务来说是一个相当大的负担。这项提议的结果可能会导致新的方向，旨在针对DETC进行未来的治疗，并研究其他受糖尿病影响的组织(如肠道)中的上皮内伽马-三角洲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.