基于银屑病血燥证“燥湿互化，湿毒内生”研究养血解毒方对Stat3介导的γδT-KC相互作用的分子机制

The mutual activation among γδ T-KC feedback loop by IL-17 stimulation in psoriasis lesion keep the immune response persist exist, in which STAT3 pathway abnormal activation play an important role in inflammation persistent. The blood-dryness differention of psoriasis attracted more attention for its long disease course and difficulty to cure. We proposed the hypothesis that blood-dryness is formed by internal dampness-poison deposition caused by abnormal transformation between dampness and dryness, by which body fluid distribution in skin is arrested and skin injury developed. It is related to pathological and physiological process of psoriasis. In clinical, nourishing blood and detoxification is the principle and Yang xue jie du(YXJD) prescription is an effective prescription. Formal studies approved that the prescription obviously improved clinical symptoms and ameliorated mice psoriasis-like lesion. Meanwhile, it inhabited Th17 cytokines secretion and suppressed pSTAT3 expression. In this project we will focus on the effect of YXJD prescription on STAT3 transgenic mice, and study the intervention onγδ T-KC loop, STAT3 pathway activation and epidermal barrier function, in order to clarify the possible targets of YXJD prescription. In vitro study, we will observe separately ‘Yang xue huo xue’ and ‘qu shi jie du’ components on the effect of γδ T and KC with STAT3 over-expression induced by stimulators, and its mutual influence and related pathway signal molecules expression, by which we explore the possible therapeutic targets of YXJD prescription from animal model, cells and molecular levels and provide scientific evidence for clinical treatment.

银屑病皮损真皮处γδ T细胞和角质形成细胞（KC）反馈环路相互激发，使IL-17为主的细胞因子群落参与持续的免疫应答，其中Stat3通路活化是炎症持续存在的重要基础。血燥证型病程绵长，经久不愈，为临床治疗难点，病机主要为燥湿互化，湿毒内生，致津液敷布异常，与银屑病病理生理变化密切相关。临床以养血解毒为法，养血解毒方显示良好的临床疗效。研究证实该方明显改善临床症状和银屑病样小鼠皮损、抑制IL-17类细胞因子分泌和pSTAT3表达。因此本项目将进一步研究其对Stat3转基因小鼠银屑病样皮损γδ T细胞、KC活化分化异常与Stat3通路调控和表皮屏障功能的作用，明确干预环节；并体外观察养血活血、祛湿解毒组分分别对诱导的高表达Stat3的IL-17+γδ T细胞、高表达Stat3的KC的活化及通路蛋白表达的影响，揭示作用靶点，从动物、细胞、分子水平阐明银屑病血燥证的病机基础，为临床治疗提供科学依据

银屑病血燥证型病程绵长，经久不愈，为临床治疗难点。其病机主要为燥湿互化，湿毒内生，致津液敷布异常，与银屑病病理生理变化密切相关。临床以养血解毒为法，养血解毒方显示良好的临床疗效。银屑病皮损真皮处γδT细胞和角质形成细胞（KC）反馈环路相互激发，使IL-17为主的细胞因子群落参与持续的免疫应答，是银屑病迁延难愈的重要原因之一，其中Stat3通路活化是炎症持续存在的重要基础。本研究在明确养血解毒方可抑制咪喹莫特诱导Stat3转基因小鼠银屑病样炎症爆发的强度及银屑病样皮损的形成、抑制IL-17类细胞因子分泌和pSTAT3表达的基础上，通过体内、外实验研究，观察Stat3通路在γδT细胞活化和迁移、KC活化和凋亡以及细胞间刺激环路形成的介导作用。深入研究养血解毒方及拆方含药血清或药物主要成分对γδT细胞、KC数量、功能及其相关信号转导通路的调节作用，明确养血解毒方作用靶点。以Stat3通路为切入点，从γδT细胞/KC异常环路的形成及养血解毒方的干预作用，构建银屑病血燥证“燥湿互化，湿毒内生”的现代分子免疫机制。进一步明确了养血解毒方通过调控γδT细胞/KC 异常活化环路和Stat3过度磷酸化发挥作用。从Stat3通路阐明养血解毒方治疗银屑病的作用机制，初步构建了银屑病血燥证“燥湿互化，湿毒内生”病机的现代分子免疫机制。