缺氧下Hsulf-1对银屑病角质形成细胞增殖的作用及其机制

Previous studies indicated that HIF-1α, a key factor in the in hypoxia microenvironment, played an important role in keratinocytes proliferation. We also found that the expressions of HIF-1a were increased in psoriasis lesion compared to normal skin and were negative correlated with Hsulf-1 expression. However, whether HSulf-1 regulating keratinocytes proliferation in the local hypoxia microenvironment of psoriasis is not yet clear. Based on this, our group tries to mimic the normaxia/hypoxia microenvironment in vivo and downregulate the expression of HIF-1a in normal skin or non-leisional skin of psoriasis patients to see the the expression change and function of HSulf-1 as a down-regulated gene;transfect the lentiviral vectors expressing HIF-1α siRNA to inhibite the expression of HIF-1α to study how HSulf-1 expression were modulated by HIF-1α to study the mechanism of HSulf-1 expression modulated by HIF-1α under hypoxia microenvironment in keratinocyte; construct psoriasis mouse model and use the transgenic Hsulf-1 overexpressed lentiviral vectors techniques to induce the expression of HSulf-1 to study the effect of HSulf-1 in keratinocytes proliferation and its function in vivo. In this way, our project tries to enriching and developing the theory of keratinocyte hyperproliferation in psoriasis under hypoxia microenvironment, elucidate the pathogenesis of psoriasis from a new perspective and offers new idea and strategies for the treatment of psoriasis.

前期研究证实缺氧微环境中关键因子HIF-1α在银屑病皮损表达较正常皮肤高，其上调与角质形成细胞Hsulf-1的表达呈负相关。然而Hsulf-1是否参与调控缺氧环境下银屑病角质形成细胞增殖尚不清楚。基于此，本课题设计模拟体内常氧／缺氧环境下调控正常皮肤或银屑病非皮损区角质形成细胞HIF－1α后，观察其下游靶基因Hsulf-1的表达和功能变化；在体外转染HIF-1α siRNA慢病毒载体阻断HIF-1α的表达，探讨缺氧环境下HIF-1α对角质形成细胞下游基因Hsulf-1转录的调控作用及其机制；构建银屑病小鼠模型，通过体内转染Hsulf-1过表达慢病毒载体，了解在体Hsulf-1生成对角质形成细胞增殖及其功能的影响。本课题通过研究，丰富和发展缺氧微环境条件下银屑病角质形成细胞增殖理论，从新的视角阐明银屑病的发病机制，为银屑病的治疗提供新的思路和策略。

本课题设计模拟体内常氧／缺氧环境下调控正常皮肤或银屑病非皮损区角质形成细胞HIF－1α后，观察其下游靶基因Hsulf-1的表达和功能变化；在体外转染HIF-1α siRNA慢病毒载体阻断HIF-1α的表达，探讨缺氧环境下HIF-1α对角质形成细胞下游基因Hsulf-1转录的调控作用及其机制。首次通过缺氧微环境研究模型，以HIF-1a为切入点，探讨其对Hsulf-1的调控，以及其对角质形成细胞增殖的作用及机制，为后续银屑病机制研究及治疗提供新的策略。通过研究，成功建立慢病毒介导的基因敲除及基因重组体的构建体系，可为银屑病后续相关基因研究，以及基因治疗研究奠定基础。