Role of epidermal lipoxygenases in congenital ichthyoses: Molecular mechanisms of pathogenesis and development of novel therapeutic approaches

常染色体隐性遗传性先天性鱼鳞病(ARCI)是一组以红斑和皮肤广泛鳞屑为特征的异质性遗传性皮肤病。已有9个不同基因的致病突变被报道，其中脂肪氧合酶基因ALOX12B和ALOXE3是最常见的突变。ALOX12B和ALOXE3分别编码表皮脂肪氧合酶12R-LOX和eLOX-3，这是皮肤代谢途径中两个紧密相连的酶组分。在患者和基因敲除小鼠中，12R-LOX/eLOX-3途径的中断导致表皮通透性屏障缺陷和鱼鳞状表型。该项目的总体目标是阐明发病的分子机制，并利用表皮、人造小鼠皮肤等效物和人类患者皮肤样本中LOX基因结构性或条件性失活的小鼠模型开发新的治疗方法。12R-LOX和eLOX-3在酰神经酰胺的加工过程中起主要作用，酰神经酰胺是皮肤屏障功能的重要结构成分。缺乏这些蛋白结合的神经酰胺是通透性屏障缺陷的主要原因。因此，我们的第一个目标是在体外和条件性基因敲除小鼠模型中评估神经酰胺在皮肤等价物上替代的药理学方法，旨在寻找局部治疗方案。在神经酰胺加工过程中释放的LOX产物被认为是有效的脂质介体。花生四烯酸的相关环氧醇衍生物，即肝素A3和B3，是12S-LOX代谢物12S-HPETE转化过程中形成的eLOX-3活性的进一步产物。我们将尝试探索这些LOX产品是否以及在多大程度上可能在正常皮肤分化期间和皮肤屏障功能丧失后作为信号分子发挥作用。第三，我们的目标是阐明在通透性屏障丧失后导致鱼鳞状表型的分子信号过程。我们将重点介绍MAP激酶在屏障缺陷引起的角质形成细胞增殖和分化变化相关基因转录调控中的作用。

The autosomal recessive congenital ichthyoses (ARCI) constitute a heterogeneous group of genodermatoses characterized by erythema and generalized scaling of the skin. Causative mutations in nine different genes have been reported, among which the lipoxygenase genes ALOX12B und ALOXE3 are frequently affected. ALOX12B und ALOXE3 encode the epidermal lipoxygenases 12R-LOX and eLOX-3, respectively, two closely linked enzymatic components of a still incompletely characterized metabolic pathway in the skin. Disruption of the 12R-LOX/eLOX-3 pathway results in a defective epidermal permeability barrier and an ichthyosiform phenotype both in patients and knockout mice. The overall aim of this project is the elucidation of molecular mechanisms of pathogenesis and the development of novel therapeutic approaches using mouse models with constitutive or conditional inactivation of LOX genes in the epidermis, artificial murine skin equivalents, and skin samples of human patients. 12R-LOX and eLOX-3 play a major role in the processing of acylceramides which are important structural components of the cutaneous barrier function. Lack of these protein-bound ceramides is the main reason for a defective permeability barrier. Our first objective, therefore, is an evaluation of pharmacological approaches to ceramide replacement on skin equivalents in vitro and in conditional knockout mouse models, aiming at a topical treatment option. LOX products released during ceramide processing are considered to be potent lipid mediators. Related epoxyalcohol derivatives of arachidonic acid, the hepoxilins A3 and B3, are further products of eLOX-3 activity that are formed during conversion of the 12S-LOX metabolite 12S-HPETE. We will try to explore, whether and to what extent these LOX products may act as signaling molecules both during normal skin differentiation and after loss of cutaneous barrier function. Third, we aim at an elucidation of the molecular signaling processes that lead to an ichthyosiform phenotype subsequent to loss of the permeability barrier. We will focus on the role of MAP kinase cascades in the transcriptional regulation of genes involved in the changes of keratinocyte proliferation and differentiation resulting from the barrier defect.