Identification of molecular mechanisms of cholestatic pruritus

瘙痒影响大约70%的胆汁淤积性肝病患者。在5%的患者中，瘙痒非常痛苦，用标准的药物治疗无法控制，甚至可能成为肝移植的主要适应症。瘙痒的分子机制尚未解决，其治疗是一个尚未满足的医学需求。最近，我们在胆汁淤积症患者的血清中发现了溶血磷脂酸(LPA)作为潜在的瘙痒原。皮内注射LPA可引起小鼠一种剂量依赖性的抓挠行为。瘙痒患者血清中LPA形成酶自体趋化因子水平升高，并与瘙痒程度呈正相关。本项目的目的是：1)确定自体趋化素酶的细胞来源；2)解开胆汁淤积过程中自体趋化蛋白表达的调控；3)分析瘙痒患者皮肤的组织形态变化；4)建立胆汁淤积性瘙痒的动物模型，以证实瘙痒与自体趋化因子和溶血磷脂酸水平升高之间的因果关系。该模型的目的将是研究治疗胆汁淤积性肝病瘙痒的新的治疗方案。目前的实验和分析将增加我们对胆汁淤积性瘙痒的理解，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.