Fam114a1调控黑素细胞生物学功能及在白癜风发病中的机制研究

The pathogenesis of vitiligo is not clear. Our research group found a rare hereditary disease pigment family and identified Fam114a1 as the pathogenic gene by genome sequencing and linkage analysis , and the gene and protein expression level decreased in vitiligo lesions, functional research showed that this gene plays a very important role in regulation of pigmentation. This project aim to clarified the mutations and expression of Fam114a1 gene in patients with vitiligo on the basis of previous studies, and the regulatory network of Fam114a1 gene should be screened by RNA-Seq and other techniques. At the same time, the possible mechanism of Fam114a1 gene on the survival of melanocytes and the key molecular and regulatory mechanism of Fam114a1 gene affecting the biological function of melanocytes will be clarified at the cytological level. And the key molecular and regulatory mechanism of Fam114a1 gene should be identified Fam114a1 conditional knockout mouse model and clinical samples.In this project, the role of Fam114a1 in the pathogenesis of vitiligo and its mechanism is expected to improve the understanding of the genetic mechanism of vitiligo and provide the basis for the new therapeutic target of vitiligo.

白癜风发病机制不清。课题组前期发现一罕见遗传性色素疾病家系，通过外显子测序及连锁分析等鉴定出其致病基因为Fam114a1。进一步研究发现该基因在白癜风皮损区水平降低，且基因功能研究证实其在调控色素产生中起十分重要的作用。本项目拟在前期研究基础上明确白癜风患者Fam114a1基因的突变及表达情况，利用RNA-Seq等技术筛选Fam114a1基因相关的调控网络；同时从细胞学水平明确Fam114a1基因参与黑素细胞功能性损伤的可能机制，深入探讨Fam114a1基因影响黑素细胞生物学功能参与白癜风发病的调控网络；通过Fam114a1条件性敲除的小鼠模型和临床样本验证Fam114a1基因影响黑素细胞生物学功能的关键分子和调控机制。本项目以遗传性色素疾病家系相关研究为线索，探讨Fam114a1在白癜风发病中的作用机制，可望提升对白癜风遗传学机制的认识，并为寻找白癜风新的治疗靶位提供依据。

白癜风是一种毁容性自身免疫性皮肤病，机制不明。课题组前期发现一罕见遗传性色素疾病家系，通过外显子测序及连锁分析等鉴定出其致病基因为Fam114A1，基因功能研究证实其在调控色素产生中起十分重要的作用。本项目进一步研究发现该基因在白癜风皮损区水平降低，通过基因过表达和抑制技术，建立Fam114A1过表达和抑制的细胞株，证实Fam114A1蛋白表达抑制可促进黑素细胞的增殖、凋亡、自噬和迁移，蛋白过表达则作用相反；同时，利用CO-IP和质谱分析，发现Fam114A1的可能互作蛋白RACK1、UQCRC2、TUMF、TIMM44、HSPA1A、HSPA1L、SLC25A13，进一步验证发现Fam114A1可负调控TIMM44，RACK1蛋白表达，正调控UQCRC2，其中RACK1蛋白调控最为显著。进一步构建RACK1蛋白抑制质粒，结果在Fam114A1抑制表达细胞中抑制RACK1蛋白的表达，可逆转Fam114A1蛋白表达抑制引起的黑素细胞增殖、凋亡、自噬和迁移的增强，证实了RACK1蛋白参与Fam114A1蛋白对黑素细胞功能的影响。由此，我们得出结论：Fam114A1蛋白参与白癜风黑素细胞生物学功能的异常，RACK1蛋白是其重要的下游调节蛋白。

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