Identification of molecular mechanisms of cholestatic pruritus

瘙痒症影响约70%的胆汁淤积性肝病患者。在5%的患者中，瘙痒是严重痛苦的，标准药物治疗无法控制，甚至可能成为肝移植的主要指征。瘙痒的分子机制尚未解决，其治疗是一个未满足的医疗需求。最近，我们发现溶血磷脂酸（LPA）是胆汁淤积患者血清中潜在的促胆汁生成剂。皮内注射LPA可诱导小鼠产生剂量依赖性抓挠行为。LPA形成酶自分泌运动因子在瘙痒患者血清中升高，并与瘙痒强度相关。该项目的目的是i）鉴定自分泌运动因子的细胞来源，ii）阐明胆汁淤积期间自分泌运动因子表达的调节，iii）分析瘙痒症患者皮肤的组织形态学变化，iv）建立胆汁淤积性瘙痒症的动物模型，以证明瘙痒症与自分泌运动因子和溶血磷脂酸水平升高之间的因果关系。该模型的目的是检查治疗胆汁淤积性肝病瘙痒症的新治疗选择。本实验和分析将增加我们对胆汁淤积性瘙痒症的理解，并提供新的治疗靶点。

Pruritus affects about 70% patients with cholestatic liver disease. In 5% of patients pruritus is seriously agonizing, uncontrollable with standard medical therapy and may even become a primary indication for liver transplantation. The molecular mechanisms of pruritus are unresolved and its treatment is an unmet medical need. Recently, we unravelled lysophosphatidic acid (LPA) as potential pruritogen in sera of cholestatic patients. Intradermal injection of LPA induced a dose-dependent scratching behaviour in mice. The LPA-forming enzyme autotaxin was increased in sera of patients suffering from pruritus and correlated with the itch intensity. The aims of this project are to i) identify the cellular source of the enzyme autotaxin, ii) to unravel the regulation of the autotaxin expression during cholestasis, iii) to analyse the histomorphological changes in the skin of patients suffering from pruritus and iv) to establish an animal model for cholestatic pruritus enabling to proof the causal relation between pruritus and increased levels of autotaxin and lysophosphatidic acid, respectively. Aim of this model will be the examination of novel therapeutic options to treat pruritus in cholestatic liver disease. The presented experiments and analyses will augment our understanding of cholestatic pruritus and offer novel therapeutic targets.