MBTPS1通过S100A7调控皮肤角化及皮肤屏障的分子机制研究

毛囊鱼鳞病是一种遗传性角化异常性皮肤病，针对皮肤角化异常和皮肤屏障功能的机制探索，将有助于我们对此类疾病发病机制的理解。前期研究中，我们利用全外显子组及Sanger测序发现该病致病基因为MBTPS1和MBTPS2基因；同时在MBTPS1基因突变型斑马鱼疾病模型和患者皮损中，发现该基因缺陷可导致皮肤完整性受损，溶酶体及线粒体异常。后续实验中，我们发现MBTPS1的相互作用候选靶蛋白S100A7；MBTPS1基因突变可导致S100A7异常升高，可能严重影响皮肤角化及屏障功能。本项目拟借助细胞株研究MBTPS1与S100A7的结合位点及作用方式，研究MBTPS1基因变异通过S100A7对表皮分化增殖、皮肤紧密连接和脂质代谢的影响；同时借助突变型斑马鱼疾病模型和患者皮损，研究基因变异对表皮分化增殖、皮肤紧密连接、脂质代谢的影响，明确该基因变异在生命体中对皮肤角化异常和皮肤屏障功能的可能分子机制。

Ichthyosis follicularis is a hereditary keratotic dysdermatosis, the research of the mechanism about skin keratinization anomalies and barrier dysfunction will help us understand the pathogenesis of such diseases at the molecular level. .In the previous study, we found that the causative genes of the disease are MBTPS1 and MBTPS2 genes by the whole exome sequencing and Sanger sequencing. In zebrafish disease models and the patient, we found the gene defect led to abnormalities of lysosome and mitochondrion, and impede the integrity of skin barrier. And we found a target interacting protein, the Protein S100-A7, which may strongly regulate skin keratinization and barrier function.. This project intends to study the binding site and binding mechanism of MBTPS1 and S100A7 in HaCaT cells and Hela cells, the effect of MBTPS1 gene mutation on epidermal differentiation and prolification, skin tight junction and lipid metabolism. Via the zebrafish disease models and the patient, we are supposed to figure out the possible mechanism of keratinization anomalies and skin barrier dysfunction in vivo caused by MBTPS1 gene mutation..The proposed studies in this application will not only allow us to advance the knowledge of molecular mechanisms in hereditary keratotic dysdermatosis, but may also provide the clinical practical importance to its diagnosis, prevention, new drug development and gene therapy.