PAR2在介导表皮通透屏障功能破坏而诱发炎症导致2型糖尿病中的作用

Type 2 diabetes is likely triggered by inflammation, characterized by insulin-limited or insensitive hyperglycemia. Elevated inflammatory cytokines, including TNF-α and IL-6, can interfere with insulin action by inhibiting insulin signaling. However, the pathomechanisms of elevated cytokine levels are unknown. Our previous study showed that disruption of the epidermal permeability barrier leads to upregulation of inflammatory cytokines in the blood. Our preliminary studies showed that disruption of epidermal permeability barrier up-regulated PAR2, TSLP, TNF-α and IL-6 in the epidermis. We hypothesized that disruption of the epidermal permeability barrier induced up-regulation of inflammatory cytokines is mediated by PAR2, leading to the development of T2DM. To test this hypothesis, we first plan to silence HaCaT cells by PAR2 siRNA. Construct a human 3D skin model. In combination with PAR2 knockout mice, the role of PAR2 in inducing inflammation in mediating the destruction of the epidermal permeability barrier was investigated at the cellular and animal levels; Second, we will determine whether improving epidermal permeability barrier and cutaneous inflammation can delay or prevent the development of T2DM in mice. We expect that the disruption of epidermal permeability barrier function accelerates the development of T2DM, while conversely improving epidermal permeability barrier function delays PAR2 the development of T2DM. Inflammation-induced by disruption of epidermal permeability barrier function is mediated by PAR2. Improving epidermal permeability barrier could be a novel preventive and therapeutic approach for T2DM.

2型糖尿病是一种以胰岛素受限或不敏感诱发高血糖为特征的炎症性疾病。TNF-α和IL-6等炎症因子上调可通过抑制胰岛素信号转导而诱发T2DM。然而，炎症因子升高的病理机制尚不清楚。我们发现，表皮渗透屏障的破坏导致血液中炎症因子的上调；预实验发现，通透屏障的破坏上调了表皮中PAR2，TSLP，TNF-α和IL-6的mRNA表达。我们提出假说：PAR2介导表皮通透屏障的破坏诱导炎症因子上调，最终导致T2DM。为了验证假说，首先我们拟用PAR2的基因敲除鼠及敲除的HaCaT细胞，构建人3D皮肤模型，研究PAR2在介导屏障破坏而诱发炎症中作用;其次，拟用T2DM模型鼠来确定改善屏障功能是否可通过降低炎症因子来预防或治疗T2DM。预计PAR2介导的屏障功能破坏加速了T2DM的发展，而改善屏障功能可抑制PAR2的激活而降低炎症反应，从而预防和治疗T2DM。改善表皮通透屏障是新的T2DM预防和治疗方法。

糖尿病是一种以胰岛素受限或不敏感诱发高血糖为特征的炎症性疾病。疾病特征的诱因与持续的炎症反应相关。炎症细胞因子TNF-α和IL-6浓度升高可通过抑制胰岛素信号转导而干扰胰岛素发挥作用。抑制持续的炎症反应是T2DM治疗的有效途径。我们前期的研究发现通过皮肤屏障的修复可有效抑制表皮及外周血中炎症因子的上调。基于此本项目以糖尿病模型BKS-Lepr-/-GPT小鼠设置屏障修复组和对照组，以BKS-Lepr+/+GPT小鼠设为野生型对照组，构建糖尿病小鼠模型，以涂抹皮肤屏障功能修复剂为干预措施，持续干预26周。综合多次重复实验的结果分析：与对照组相比，皮肤屏障功能修复剂可有效改善糖尿病小鼠的表皮功能指标，如角质层含水量、经皮水分丢失速度、表皮酸碱度。皮肤屏障功能的修复也降低了炎症因子的表达。与对照组相比，皮肤屏障修复组糖尿病小鼠表皮中PAR2及TNF-α的表达量显著低于对照组。小鼠血液中检测与糖尿病相关的炎症因子表达TNF-α、IL-6也显著低于对照组。小鼠脾脏指数的检测结果也显示：皮肤屏障修复可有效改善糖尿病小鼠的脾脏指数。同时，糖尿病的两个主要参考指标血糖值和胰岛素耐受的检测结果也证实，皮肤屏障功能修复可有效延缓糖尿病小鼠血糖值的升高及胰岛素耐受的加重。综合上述结果，皮肤屏障功能修复可通过抑制表皮中PAR2的激活从而抑制下游的炎症通路的上调，从而延缓糖尿病的加重。皮肤屏障的修复可能作为未来潜在的糖尿病辅助治疗及预防发病的新方向。根据该项目资助的研究成果发表英文论文两篇，中文论文一篇。项目投入经费20万元，支出经费19.84万元，各项支出基本与预算相符。本项目后续将会持续开展进一步的研究，为糖尿病的预防与治疗提供支持。