基于"三焦气化则湿亦化"理论研究FABPs-PPARs通路在特应性皮炎发病机制中的作用

Atopic dermatitis is a common hereditary and autoimmune disease in children. Chinese medicine believes that it is due to spleen deficiency and the pathogenic factors of wind、dampness and hot in the skin. We believe that the process of AD's repeated attacks and mitigation just reflects the apparence of san jiao. It also means that the barrier defects of FLG-PPARα would lead to the oxidative stress and immune injury mediated by the signaling pathway of A-FABP-PPARγ. The pathological changes of of blood deficiency and wind dryness occur in the signaling pathway of E-FABP - PPARβ/δ after the long-time course of AD.This study is a case-control study in AD patients and Nc/Nga mice, the methods of fluorescent quantitative RT-PCR immunohistochemistry and FISH will be used to study the expression of FABPs-PPARs signaling pathway and its downstream effectors in different stages of AD. The findings could reveal the pathogenesis molecular mechanisms of AD from the gene-disease-syndromes angle, and they could also provide a new theoretical basis for the scientific connotation of san jiao and wind、dampness and hot in the skin, so as to expand new train of thinking of the objective TCM Syndrome and scientific individualized treatment of AD.

特应性皮炎（atopic dermatitis，AD）是一种儿童常见的遗传、免疫性疾病，中医认为是由于脾虚不足为本，外加风、湿、热诸邪相搏于皮肤而发病。我们认为AD 反复发作和缓解的过程，正是在先天禀赋不耐（FLG-PPARα屏障功能缺陷）基础上三焦气化不及以至湿热内蕴和脾虚湿盛（A-FABP-PPARγ介导氧化应激和免疫损伤）相互交替起主导作用的结果；长期病程导致血虚风燥（E-FABP-PPARβ/δ介导表皮重构）。本研究拟采用病例对照研究方法，在AD患者和Nc/Nga小鼠中运用Q-RT-PCR、免疫组化和FISH 等方法研究FABPs-PPARs通路在不同AD证候中的调控机制，从而探明AD 的病程进展规律。本研究结果从基因-疾病-证候相关角度揭示AD 发病的分子机制，为"三焦气化则湿亦化"和"风湿热邪客于肌肤"理论科学内涵提供依据，为AD 中医辨证的客观化以及科学个体化治疗拓展新思路。

特应性皮炎是一种与遗传过敏因素有关的慢性炎症性皮肤病，病因尚不完全清楚中医治疗效果好但辩证棘手。我们通过收集不同AD证候患者的血液和皮损标本，运用荧光定量RT-PCR方法、流式细胞术和免疫组化等技术对其Th1/Th2和Th17/Treg等T细胞亚群及细胞因子进行检测，结合AD小鼠模型在不同PPARs激动剂干预前后的实验结果， 对比分析FABPs-PPARs通路在不同AD证型中的作用特点。研究结果表明FABPs-PPARs分子表达谱在AD患者中存在差异表达，且与不同中医证型密切相关，这些差异表达可能是三焦气化亦湿化的物质基础。我们发现PPARγ分子则主要是在湿热内蕴组中表达，是AD患者皮肤氧化应激和免疫损伤的主导因素，其上游调控基因与miR-203a密切相关；临床标本和双荧光素酶报告基因检测（靶基因验证）分别验证了PPARγ与miR-203a及PDE4D与miR203a的关系，结果显示PDE4D可能是PPARγ下游通路的关键靶基因，是治疗包括AD在内的许多难治性皮肤病的关键药物靶点之一。PPARs信号通路作为一种皮肤内环境稳定系统，在AD炎症反应的各个证型都发挥重要的整体调控作用，其差异表达可为AD 中医微观辨证的客观化以及科学个体化治疗拓展新思路。