原发性皮肤淀粉样变（PCA）是淀粉样物质沉积于皮下伴随瘙痒的慢性皮肤病，角质形成细胞（KC）分泌学说是其发病的主流学说，但具体机制尚不清楚。研究报道，OSMR突变是PCA的主要致病因素，项目组前期研究证实pG513D和pP694L是PCA患者OSMR基因主要突变型。预实验发现：（1）OSM能激活STAT5，抑制KC分化，OSMR pG513D和pP694L突变能解除OSM对KC分化的抑制作用；（2）OSMR突变PCA患者皮损区KC分化的角蛋白标志物表达增加，Ki67+基底层KC比例增加。据此，我们提出以下假说：OSMR功能缺失突变解除OSM对基底层KC增殖与分化的抑制作用参与PCA的发生。本项目旨在通过Osmr点突变小鼠结合ATAC-seq等技术，在细胞和动物水平揭示OSMR突变调控KC增殖与分化参与PCA发生的分子机制，进一步在患者皮损组织中进行验证，为PCA的临床治疗提供新策略和新靶点

Primary localized cutaneous amyloidosis (PCA) is a skin-limited disorder characterized by deposition of amyloid material in the superficial dermis. Keratinocyte secretion is the major pathogenic theory of PCA, but the detail mechanisms are remained to be elusive. Missense mutations of OSMR have been identified as one of the pathogenic genes for PCA. Our previous studies found that pG513D and pP694L mutations of OSMR have a higher incidence rate in Chinese PCA patients. Our preliminary data indicated that: (1) OSM inhibits keratinocytes differentiation via STAT5 signaling pathway, and pG513D and pP694L mutations cause the loss-of-function of OSMRβ in keratinocytes; (2) PCA patients with OSMR mutation exhibit enhanced epidermal keratinocytes proliferation and differentiation. We speculated that OSMRβ mutants enhance keratinocytes proliferation and differentiation in PCA patients. This project aims to elusive the potential mechanisms on keratinocytes proliferation and differentiation regulated by OSM via high-throughput sequencing. Skin samples of PCA patients and OsmrpG510D mice were also used to explore the pathogenic mechanisms in PCA, in order to provide new strategies and targets for clinical treatments.