Epigenetic alterations of TA-keratinocytes as underlying cause of hyperproliferation in psoriasis

TA-角质形成细胞的表观遗传改变是银屑病过度增殖的根本原因

• 批准号: 408014262
• 负责人: Dr. Katrin Witte
• 金额: --
• 依托单位: Berlin-Brandenburger Centrum für Regenerative Therapien (BCRT)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/408014262?language=en
• 关键词: Epigenetic; alterations; TA; keratinocytes; underlying

Psoriasis is a chronic inflammatory skin disease, that is characterized by the presence of erythematous, highly scaling skin lesions, affecting about 1.6-2.4 million people in germany alone.As a complex multifactorial systemic disease, psoriasis, which is very stigmatizing from the patients´ perspective, entails a substantial physiological and psychological suffering and has a high socio-economical relevance. It is known for a long time, that the cutaneous inflammatory processes in psoriasis are accompanied by a highly increased division rate (hyperproliferation) and decreased differentiation of epidermal keratinocytes. In fact, the duration of basal keratinocytes to reach the skin surface in the differentiated corneocyte state is shortened from 28 days in healthy people to 3-5 days in psoriasis patients. Considering the severity and prevalence of this disease, the therapeutic options are actually limited to throughout symptomatic approaches that cause significant clinical improvement only in a proportion of patients without showing long-lasting effectiveness. A sustained normalization of the keratinocyte biology, especially of the pathologically increased proliferation, is a huge clinical challenge in dermatology and can only be targeted by a causal therapeutic approach. For the development of such an approach, detailed information regarding the proliferation aspect on the molecular level is essential. Currently the underlying knowledge in this field is sparse however. Even though recent research supports an involvement of epigenetics in psoriasis pathogenesis, the only published data in this regard do not allow an assignment to a certain cell type of the skin. Based on an established cell sorting protocol, we could already show, that the mitotically active keratinocyte fraction (transit amplifying cells, TAC) obtained from psoriasis patients show substantial differences in their methylome and transcriptome pattern with significant overlap between both omics.

银屑病是一种慢性炎症性皮肤病，其特征是皮肤出现严重的鳞屑性皮损，仅在德国就有160 - 240万人患病。银屑病是一种复杂的多因素系统性疾病，患者对它的认知非常模糊，它给患者带来了巨大的生理和心理痛苦，并具有很高的社会经济意义。长期以来，已知银屑病中的皮肤炎症过程伴随着表皮角质形成细胞的分裂速率（过度增殖）的高度增加和分化的降低。事实上，基底角质形成细胞在分化的角质形成细胞状态下到达皮肤表面的持续时间从健康人的28天缩短到银屑病患者的3-5天。考虑到这种疾病的严重程度和患病率，治疗选择实际上仅限于整个对症方法，这些方法仅在一部分患者中引起显著的临床改善，而没有显示出持久的有效性。角质形成细胞生物学的持续正常化，特别是病理性增加的增殖，是皮肤病学中的巨大临床挑战，并且只能通过因果治疗方法来靶向。 为了发展这种方法，在分子水平上关于增殖方面的详细信息是必不可少的。然而，目前在这一领域的基本知识是稀疏的。尽管最近的研究支持表观遗传学参与银屑病发病机制，但在这方面唯一发表的数据不允许将其分配给皮肤的某种细胞类型。基于建立的细胞分选方案，我们已经可以表明，从银屑病患者获得的有丝分裂活性角质形成细胞部分（转运扩增细胞，TAC）在其甲基化组和转录组模式中显示出实质性差异，两个组学之间具有显著重叠。