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）存在于鼠皮肤中，在那里它们监测上皮细胞的损伤。DETC表达单克隆γ-δ T细胞受体（TCR），其用于识别由受损或应激的角质形成细胞表达的未知抗原。我们以前已经表明，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（KGF）在皮肤稳态和伤口修复中发挥作用。在糖尿病小鼠和人类中的工作表明，伤口部位IGF-1和KGF水平的降低有助于受损的伤口修复。我们推测，受损的生长因子的生产和缺陷的角质形成细胞在糖尿病伤口的增殖是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在糖尿病伤口中是否起作用。此外，我们将研究哪些机制可能导致糖尿病中DETC功能障碍，包括：胰岛素受体（IR）信号传导的变化，糖皮质激素的抑制，以及IGF-1受体（IGF-1 R）信号传导的减少。通过了解糖尿病小鼠伤口愈合过程中DETC-角质形成细胞的串扰，我们可能会发现新的机制，可以利用这些机制来提高伤口修复的效率，并提供对IR和IGF-1 R信号传导时间的了解。所提出的实验本质上是探索性的，并且涉及伤口修复的I型和II型糖尿病小鼠模型。糖尿病不愈合伤口是一种使人衰弱的并发症，治疗是卫生服务的一个相当大的负担。这一提议的结果可能会导致新的方向，旨在靶向DETC用于未来的治疗，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.