ADAM17介导EGFR信号通路在中耳胆脂瘤角质形成细胞过度增殖中的机制研究

ADAM17是一种跨膜金属蛋白酶，可通过蛋白水解作用剪切、脱落出多种EGFR配体，从而激活EGFR相关增殖性信号通路，是EGFR信号通路的“启动者”。中耳胆脂瘤是以角质形成细胞过度增殖为特征的疾病，其增殖的内在分子生物学机制不明。我们前期研究发现EGFR信号通路在中耳胆脂瘤上皮组织中处于激活状态，在胆脂瘤角质形成细胞过度增殖中起关键作用，但其激活的具体作用机制尚未明确，ADAM17是否参与其中目前尚无文献报道。由此，我们首次提出如下假说：ADAM17在中耳胆脂瘤中处于激活状态，并通过剪切、脱落出多种EGFR配体进而激活EGFR相关增殖性信号通路，最终导致胆脂瘤角质形成细胞过度增殖。本课题将通过体内、外实验揭示ADAM17介导EGFR信号通路在中耳胆脂瘤角质形成细胞过度增殖中的作用，为明确中耳胆脂瘤角质形成细胞过度增殖的内在分子机制提供实验依据，并为防治中耳胆脂瘤上皮过度增殖开辟新思路。

ADAM17 belongs to a disintegrin and metalloproteases (ADAMs) family of typeⅠ transmembrane Zn2+-dependent proteases that play a role in the proteolytic ectodomain shedding of multiple membrane-tethered ligands and cytokines implicated in diverse biological processes, including growth and inflammation. It has protease activity against multiple epidermal growth factor receptor (EGFR) ligands, thus activating EGFR-related proliferative signaling pathway. Cholesteatoma is a pathological condition characterized with keratinocyte hyper-proliferation, however, the molecular mechanism underlying the pathogenesis of cholesteatoma remains unknown. Our previous studies have demonstrated that EGFR signaling pathway is active in cholesteatoma and may play a crucial role in keratinocyte hyper-proliferation. However, the mechanism of the EGFR signaling pathway activation in cholesteatoma remains unknown, and whether ADAM17 participants in the activation is unreported. Accordingly, we hypothesize that ADAM17 may be activated in cholesteatoma tissues, and involved in the activation of EGFR signaling pathway through cleaving and releasing various EGFR ligands, leading to the keratinocyte hyper-proliferation responsible for cholesteatoma. In this study, we will investigate the role of ADAM17-mediated EGFR signaling pathway in the keratinocyte hyper-proliferation of cholesteatoma through in vivo and in vitro experiments. So that it could clarify the molecular mechanism of keratinocyte hyper-proliferation and explore a novel target for the prevent and treatment of keratinocyte hyper-proliferation of middle ear cholesteatoma.