中国汉族重型痤疮易感基因SELL及DDB2的表达及蛋白功能研究

Severe acne is a common, harm, complex major diseases which bring physical and psychological effects on patients. It also cause society problems. Studies have shown that acne is a polygenic disease and genetic factor plays an important role in severe acne. Several studies demonstrated that a number of genes involving androgen metabolism and cytokines pathway were associated with acne. Severe acne susceptibility genes and its functions haven't been fully understood, which impedes early diagnosis and effective treatment of severe acne. We carried out researches of acne genetic model and relationship between 8 androgen pathway genes and acne; we also established severe acne genetic resources base in China. Our previous works identified two new susceptibility genes confer risk to severe acne by a genome-wide associated study in 2916 cases and 4716 controls in Chinese Han population. We will carry detect the system and local expression of the two susceptibility genes in patient and controls, and also demonstrate functions of those two genes in severe acne. These works will provide an important evidence for the pathogenesis of severe acne, as well as the research and development of early diagnostic reagents for the disease.

重型痤疮是一种危害大、易复发的常见复杂疾病，早期诊断及有效治疗仍是临床上难以攻克的难点,给患者带来巨大身心危害并造成社会问题。国内外研究表明重型痤疮与遗传密切相关，多个涉及雄激素代谢和细胞因子通路的基因主要与重型痤疮发病相关，但缺少蛋白功能研究，易感基因尚未明确，申请人及团队前期开展了痤疮遗传模式研究；雄激素通路8个基因与痤疮相关性的研究；建立了中国汉族重型痤疮遗传资源库；并通过对2916例重型痤疮及4716健康对照的GWAS初筛和验证研究，发现了两个新的易感基因SELL及DDB2与中国汉族重型痤疮密切相关,但其基因功能及致病机理尚未明确。本课题将在前期研究基础上，全面探讨SELL及DDB2在患者和对照中的系统及局部表达水平，深入分析SELL及DDB2表达变化对细胞及鼠耳炎性痤疮模型的影响，揭示两个易感基因的表达及蛋白功能在疾病发生中的分子机制，为疾病早期诊断试剂开发及靶向治疗提供理论依据

重型痤疮是一种危害大、易复发的常见复杂疾病，早期诊断及有效治疗仍是临床上难以攻克的难点,给患者带来巨大身心危害并造成社会问题。本课题在全基因组关联分析发现重型痤疮2个新易感基因的前期基础上，全面开展易感基因SELL及DDB2在重型痤疮和健康对照中的系统及局部表达水平研究，深入分析SELL及DDB2表达变化对细胞及动物模型的影响，探讨易感基因在重型痤疮中可能的作用及机制。项目明确了SELL基因在重型痤疮患者外周血白细胞中mRNA的表达、血清中可溶性蛋白的表达及局部痤疮皮损的表达均显著高于健康对照组；DDB2基因在重型痤疮患者血清中蛋白的表达及局部痤疮皮损的表达均显著低于健康对照组。阐明了DDB2在基因的下调可导致痤疮效应细胞角质形成细胞增殖活跃，并通过上调P65蛋白的表达激活NF-kB信号通路，从而在痤疮丙酸杆菌刺激的细胞中增加IL-6、IL-8等细胞因子的表达，提示DDB2基因可通过影响角质形成细胞增殖及P.acne诱导下炎症因子的表达而参与重型痤疮的炎症过程。SELL基因在重型痤疮中表达上调，其表达上调与痤疮丙酸感染所致的炎症相关，作为粘附分子家族成员，可能通过募集炎症细胞到痤疮皮损处而参与痤疮的发生。本研究揭示了重型痤疮两个易感基因SELL及DDB2的系统及局部表达水平，并探讨了易感基因及其蛋白在重型痤疮发生中可能的作用及机制，结果有助于了解重型痤疮的发病机制，并为疾病早期诊断试剂开发及靶向治疗提供理论依据。