原发性皮肤淀粉样变（PCA）是淀粉样蛋白沉积于皮肤而无其他器官受累的慢性瘙痒性皮肤病，角质细胞凋亡是其发病机制的主流学说，但具体机制不明。目前发现OSMR基因突变是家系PCA患者的主要病因，我们前期研究也发现OSMR基因突变率在家系患者高达63.89%、在散发患者也达到34.38%；免疫荧光和Western blot检测结果显示PCA皮损处基底膜整合素α6β4表达显著降低；OSMR基因敲低的人角质形成细胞（原代和细胞系）α6表达较对照细胞显著下调；而文献报道α6β4能够保护上皮细胞抵抗铁死亡，且本项目预实验显示患者皮损和OSMR敲除小鼠皮肤中铁死亡关键蛋白ACSL4表达高于正常皮肤。据此，我们提出“OSMR通过调控α6介导角质形成细胞铁死亡参与PCA发病机制”的假说。本项目将从分子、细胞和基因敲除动物实验深入研究阐明OSMR如何导致PCA发生的分子机制，为寻找新的PCA治疗靶点奠定基础。

Primary cutaneous amyloidosis (PCA) is a chronic pruritic skin disorder associated with amyloid deposits in the superficial dermis, with no systemic involvement. The mainstream theory thinks that the amyloid in PCA is derived from keratin after epidermal damage and keratinocyte apoptosis, while the pathomechanism of PCA still remains unclear.The missense mutations in the oncostatin M receptor (OSMR) gene have been identified as the major cause of familial primary cutaneous amyloidosis. In our previous study, we found OSMR missense mutation rate was 63.89% in familial patients, 34.38% in sporadic patients. Moreover, analysis of α6β4 integrin levels in human skin samples has shown increased expression of α6β4 in PCA patients compared with healthy control populations. Moreover, the α6 expression was markedly reduced in the OSMR-knock down human primary keratinocyte and HaCaT cell line when compared with the control cell. While the α6β4 integrin was reported to protect adherent epithelial cells from ferroptosis. Forthermore,our preliminary data showed that the expression of ACSL4 (Acyl-CoA synthetase long-chain familymember4),an essential component for ferroptosis execution , was higher in PCA patients than in heathy control, also substantialy increased in OSMR-knock out mice than in wild type mice. Therefore, we hypothesize that mutant OSMR can induce ferroptosis of basal layer keratinocyte mediated by downregulating the α6 integrin ,and lead to PCA finally. We plan to explore the molecular mechanism of PCA through clinical cases, cell model and OSMR knock out mouse model.