miRNA-30a-3p影响IGF-1相关通路在反常性痤疮发病中的机制研究

The mutation of nicastrin (NCT), which is a subunit of γ-secretase, has been confirmed to be closely associated with familial acne inversa (AI), but its biological function during the process of AI remains unclear. As the hair follicle clumps induced by abnormal follicular epithelial dysplasia is considered to be a driving factor of AI, and previous results showed that loss expression of NCT could promote abnormal proliferation of keratinocytes, this project attempts to elucidate the relationship between NCT mutation and the pathogenesis of AI via studying how NCT/γ-secretase regulates microRNA (miRNA) level and the following signaling pathway. Combined with miRNA microarray data from familial AI patients and NCT-specific knockout mice and bioinformatics predictions, this subject will study the molecular mechanism of the promoting effects of NCT mutation/γ-secretase dysfunction mediated signaling pathway (NCT/miR-30a-3p/IGF-1) on keratinocyte abnormal proliferation. We will also elucidate the biological function of the above mentioned pathway in AI process. The subject will not only contribute to deepen understanding of the pathogenesis of AI, but also provide novel clues for the clinical treatment of AI.

γ-分泌酶中nicastrin（NCT）亚基的突变已被证实与家族性反常性痤疮（AI）密切相关，但其在AI发病过程中的功能尚未完全明确。基于毛囊上皮细胞异常增生导致的毛囊堵塞是反常性痤疮（AI）的始动因素，同时前期结果发现NCT表达缺失促进角质形成细胞异常增殖，申请人拟从NCT/γ-分泌酶通过改变微小RNA（miRNA）水平影响相关信号通路的角度来研究NCT与AI发病的联系。通过分析家族性AI病人以及NCT特异性敲除小鼠皮损miRNA芯片结果并进行生物信息学预测，本项目将研究NCT突变导致的γ-分泌酶功能缺失可通过调控miR-30a-3p水平激活胰岛素样生长因子（IGF-1）介导的信号通路，最终促进角质形成细胞异常增殖的分子机制，并进一步阐明上述通路在AI发病过程中发挥的作用。该研究不但有助于加深对AI的发病机制的认识，也为AI提供全新的可能干预靶点和治疗思路。

γ-分泌酶中NCT亚基的突变已被证实与家族性反常性痤疮密切相关，但其在家族性反常性痤疮发病过程中的功能未完全明确。由于毛囊上皮细胞异常增生导致的毛囊堵塞是家族性反常性痤疮的始动因素，我们前期结果已发现NCT表达缺失促进角质形成细胞异常增殖和分化，通过转录组测序、miRNA芯片及基因敲除小鼠模型等实验手段研究，发现家族性反常性痤疮和角质形成细胞特异性敲除NCT的模型小鼠皮损中miR-30a-3p和miR-100a-5p的表达水平均下降，进一步发现NCT可通过miR-30a-3p/RAB31轴促使EGFR降解，导致角质形成细胞分化异常，该研究首次揭示了明星分子EGFR信号通路在家族性反常性痤疮中的重要作用，为家族性反常性痤疮的研究和临床治疗提供新的靶点和思路。. 同时我们发现NCT突变可以削弱miR-100-5p，进而激活AKT通路，促进角质形成细胞的过度增殖。另外在细菌感染方面，我们发现痤疮丙酸杆菌来源的生物膜可通过miR-146a影响NF-κB等通路来调控皮肤炎症反应，揭示了机体代偿性增加的miR-146a可通过阻断角质形成细胞中TLR2/IRAK1/TRAF6/NF-kB通路和MAPK信号通路来抑制生物膜诱导角质形成细胞的炎症反应，相关工作阐释了若干微小RNA及相关通路在毛囊皮脂腺炎症中的生物学功能，从而为发展针对痤疮等毛囊皮脂腺炎症的疗法开辟新的道路。