角蛋白K24在斑秃发病中的作用及机制研究

Alopecia areata (AA) is a common, inflammatory, nonscarring type of hair loss. Patients affected by AA encompass all age groups, sexes, and ethnicities, and may experience frustration with the unpredictable nature of their disease for which there is currently no definitive treatment. The cause of AA remains incompletely understood, though it is believed to result from a loss of immune privilege in the hair follicle, autoimmune-mediated hair follicle destruction, and the upregulation of inflammatory pathways. Patients with AA frequently experience marked impairment in psychological well-being, self-esteem, and may be more likely to suffer from psychiatric comorbidities. However, there are many side effects of current oral and topical medications. Therefore it is desirable and urgent to furtherly understand the mechanism of AA and find more safe and effective treatments. Keratin 24 is a new kind of keratin. It is a cytokeratin-like protein of 525 amino acids, belongs to type I keratin polymers. K24 is reported to be highly expressed in keratinocytes, placenta, colon and spleen. Recent experimental studies have pointed to newly recognized roles of certain keratins in apoptosis, cell growth, tissue polarity, wound response, and tissue remodeling. Our latest research show that K24 participates cell senescence and apoptosis through autophagy. Meanwhile we also found the AA-like manifestation on the overexpressed Krt24 transgenic (Krt24-GFP) mice. Previous studies demonstrated the key roles of autophagy in epidermal differentition and hair growth. Therefore we hypothesize that: K24 may mediate hair growth cycle and participate the pathogenesis of AA. This project aims to investigate the expression and function of K24 in AA by employing AA scalp ex vivo, primary hair follicle cell cuture in vitro and transgenic mouse model in vivo. In conclusion, through this study, we may find novel pathway to the pathogenesis of AA and possible novel target to future therapy.

斑秃（AA）是引起炎症性脱发的最常见原因，可发生于任何年龄，其发病机制不明确。AA患病率极高，对生活质量特别是心理精神层面影响极大，而现有治疗方法非常有限，治疗药物存在较大不良反应。因此，深化对斑秃发病机制的认识和理解，从而找到更加安全有效的治疗方法是当前医学研究的重要课题。角蛋白24（K24）是一种新型角蛋白，在表皮、胎盘、结肠及脾脏中表达丰富。角蛋白可参与多种生物学行为，包括调节细胞生长、迁移及凋亡等。我们最新研究表明：K24可通过自噬诱发角质形成细胞衰老和凋亡。同时也发现：K24转基因小鼠背部出现脱毛，有自愈倾向，与斑秃表现非常类似。既往研究表明：自噬在表皮及毛发生长中有着非常重要的作用。因此我们推测：角蛋白K24很可能参与毛发生长调节，介导转基因小鼠的斑秃样损害。本研究拟通过离体皮损、体外毛囊细胞培养以及转基因小鼠模型实验，探索K24在斑秃发病中的机制及意义，以期发现新的治疗靶点。

我们之前的研究表明，角蛋白24（K24）可以诱导角质形成细胞的衰老和凋亡。在K24转基因小鼠的构建中，我们观察到可逆的脱发现象。此外，免疫荧光表明K24在小鼠毛囊的外根鞘和毛干中显着表达。因此，我们打算研究K24在脱发中的作用。结果表明，K24在脱发区表达量高，与β-连环蛋白的趋势相反，同时与IL-1α一致。此外，K24的表达在毛囊周期中周期性地发生变化，在生长期中较高，在减退期中下降，在休止期中较低。总体而言，这些发现表明K24可能会影响毛囊周期和头发结构。