REGγ-蛋白酶体系统在毛发生长中的调控作用及分子机制

The premature senescence of hair follicles with phenotypes such as hair yellowness and lack of hair has become a disease that seriously affects the quality of life of human beings. At present, there is no cure, and the pathogenesis is still unknown. REGγ acts as a proteasome activating factor capable of mediating proteasome degradation of substrate proteins in a non-ATP and ubiquitination manner, and its function is widely recognized in the fields of tumor, immunity, metabolism, and infection. Our previous study found that REGγ knockout (KO) mice developed symptoms such as baldness, brown hair, and hair follicle atrophy. Preliminary results showed that the hair follicle cycle of KO mice was prolonged and the number of hair follicle stem cells was reduced. To elucidate the role of REGγ in hair growth and its molecular regulation mechanism, we will screen out new REGγ target proteins by proteomics and regulate the hair follicle cycle in the REGγ-mediated pathway of the candidate proteins LHX2 and Lgr5. The role and mechanism of stem cell dry maintenance was studied. Finally, we will determine the unknown biological function in model animals by exploring the effects of REGγ deficiency on mouse hair follicle homeostasis. This study will provide a new theoretical basis and target for the diagnosis, treatment and drug development of diseases related to hair follicle homeostasis.

以毛发缺如、枯黄等病症为表型的皮肤毛囊问题已成为严重影响人类生活质量的疾病，因发病机制未知，目前尚无根治手段。REGγ作为能够介导底物以非ATP和非泛素化方式降解的蛋白酶体激活因子，其功能在肿瘤、免疫、代谢等领域受到了广泛认可，也有文献预测REGγ在干细胞领域发挥作用，但尚未找到实质性证据。我们前期研究发现REGγ敲除（KO）小鼠会出现被毛斑秃、毛色发黄、毛囊萎缩等症状。初步研究显示KO小鼠毛囊静止期延长，毛囊干细胞数量减少。为阐明REGγ在毛发生长中的作用及分子调控机制，我们将以前期通过蛋白质组学筛选出来的新的REGγ靶蛋白—-LHX2在REGγ介导的通路中对毛囊周期调控，毛囊干细胞干性维持中的作用和机制展开研究。最终，我们将通过探索REGγ缺失情况下对小鼠毛囊稳态的影响来确定其在模式动物体内的生物学功能。这项研究将为毛发周期异常和皮肤衰老等疾病的防治、药物开发提供新的理论依据和靶点。

背景:REGγ作为蛋白酶体激活因子，以不依赖于ATP和泛素化的方式介导蛋白酶体降解底物蛋白，同时也是细胞周期、增殖和凋亡的重要调节因子。毛发周期包括三个动态的、连续的形态变化阶段(发育期、休止期和发育期)。REGγ在毛发循环中的作用尚不清楚。.主要研究内容:采用REGγ敲除293T细胞、诱导293WT和293N151Y细胞、REGγ敲除小鼠，研究REGγ调控毛囊干细胞的分子机制。.重要结果和关键数据:在本研究中，我们发现REGγ缺失显著延缓了小鼠毛囊从休止期到休止期的转变和毛发再生。我们还观察到毛囊干细胞数量、细胞干性和增殖能力显著降低。real-time PCR、FACS、Western Blot和免疫荧光分析结果显示，REGγ缺失可显著下调毛囊中Lgr5的表达。同时，REGγ被证明与LHX2直接相互作用并促进其降解。重要的是，Lgr5+干细胞中REGγ特异性缺失导致脱毛后毛发再生明显延迟。.科学意义:上述数据表明REGγ是Lgr5在毛囊中表达的新介质，至少部分通过促进其抑制转录因子LHX2的降解来实现。REGγ似乎通过激活Lgr5阳性毛囊干细胞来调节毛发生长原进入和毛发再生。