Wnt-associated Dkk3 in inflammatory and fibrosing skin disease (C06)

放射性皮炎可引发慢性炎症/纤维化过程。我们发现Dickkopf-3(Dkk3)，一种与免疫调节有关的Wnt相关蛋白，在辐射损伤的小鼠模型中促进慢性纤维化炎症。Dkk3基因敲除不会发生表皮增生或慢性真皮成纤维细胞/炎症激活。该建议旨在(I)使用报告鼠和靶向Dkk3基因敲除来确定辐射损伤皮肤中Dkk3的相关细胞来源，(Ii)表征Dkk3对局部巨噬细胞和T细胞的影响，(Iii)使用人类皮肤模型剖析Dkk相关信号通路的影响，以及(Iv)将辐射诱导的表观遗传修饰与Dkk3的表达和慢性炎症纤维化联系起来。

Radiation dermatitis can initiate a chronic inflammatory/fibrosing process. We found that Dickkopf-3 (Dkk3), a Wnt-related protein linked to immune regulation, promotes chronic fibrosing inflammation in mouse models of radiation damage. Dkk3 knockouts do not develop epidermal hyperplasia, or chronic dermal fibroblast/inflammatory activation. The proposal seeks to (i) identify the relevant cellular source of Dkk3 in radiation damaged skin using reporter mice and targeted Dkk3 knockouts, (ii) characterize Dkk3 effects on local macrophages and T cells, (iii) dissect the impact of Dkk-related signalling pathways using human skin models, and (iv) connect radiation-induced epigenetic modifications to expression of Dkk3 and chronic inflammatory fibrosis.