New Therapy for the Treatment of Primary Biliary Cholangitis.

项目摘要 原发性胆管炎(PBC)是一种肝脏小胆管受损的慢性疾病 发炎并最终被摧毁。当胆管耗尽时，由此产生的胆汁积聚会导致肝脏。 损伤，导致疤痕形成、肝硬变，最终导致肝功能衰竭。PBC的常见早期症状包括 皮肤发痒(瘙痒)、疲倦、腹痛、食欲不振、体重减轻和关节炎。这个慢性病 胆汁淤积性肝病主要影响四六十岁的女性。目前正在治疗中 治疗PBC的选择有限，许多药物治疗仅限于疾病的治疗 症状学。 溶血磷脂酸(LPA)是一种强有力的信号分子，对许多 不同的靶组织，并作为一种有丝分裂原，主要通过LPAR1参与肿瘤的发生发展 不同器官的纤维化。LPAR1也与关节炎的发生有关。其中很多都观察到了 其作用似乎涉及LPAR1的激活和通过许多 信号分子包括肿瘤坏死因子α、干扰素γ、白介素17、结缔组织生长因子和转化生长因子β。干扰素γ和IL-17是信号分子 与PBC的发展有牵连。瘙痒是与PBC相关的一种严重症状，PBC已被 与自体趋化蛋白有关，自体趋化蛋白是一种负责血浆LPA产生的酶。LPA可能通过其对神经元的作用 以LPAR1为主要受体表达的受体。因此，LPAR1可以表示 出现病理性炎症和严重的生活质量症状。 EpiGen已经确定了几类有效的和选择性的LPAR1拮抗剂，最初的 先导化合物EPGN696和备用EPGN2154在其他疾病中显示出临床前的疗效 模特们。这些化合物在人体细胞肝毒性模型中没有显示出胆汁淤积风险 一种临床化合物BMS-986020，已被撤回。我们建议分析两个LPAR 1 拮抗剂对炎性信号分子干扰素γ和IL-17的调节作用 以及临床前模型中的瘙痒反应。 完成导联分析将选择单个导联，该导联将在临床前评估 PBC模型，在加州大学戴维斯分校进行。这些研究将确定 开发一种治疗PBC的LPAR1拮抗剂。

Project Summary Primary biliary cholangitis (PBC) is a chronic disease in which the small bile ducts in the liver become injured and inflamed and eventually destroyed. When bile ducts are depleted, the resulting bile build up results in liver damage, leading to scarring, cirrhosis, and eventually liver failure. Among the common early symptoms of PBC is itchy skin (pruritus), tiredness, abdominal pain, low appetite, weight loss and arthritis. This chronic cholestatic liver disease predominantly affects women in their fourth and sixth decades. Currently therapeutic options to treat PBC are limited and much of the pharmacotherapy is restricted to management of disease symptomology. Lysophosphatidic acid (LPA) acts as a potent signaling molecule with wide-ranging effects on many different target tissues, and is implicated as a mitogen acting mainly through LPAR1 in the development of fibrosis in various organs. LPAR1 is also implicated in the development of arthritis. Many of these observed effects appear to involve LPAR1 activation and modulation of inflammatory responses through numerous signaling molecules including TNFα, IFNγ, IL-17, CTGF and TGFβ. IFNγ and IL-17 are signaling molecules implicated in the development of PBC. Pruritus is a serious symptom associated with PBC which has been linked to Autotaxin, the enzyme responsible for plasma LPA production. LPA may act on neurons through its receptors of which LPAR1 is the principal receptor expressed. Thus, LPAR1 may represent a key locus in the development of both pathologic inflammation and serious quality of life symptoms. Epigen has identified several classes of potent and selective LPAR1 antagonists from which an initial lead compound EPGN696 and backup EPGN2154 have demonstrated pre-clinical efficacy in other disease models. These compounds do not show cholestatic risk in human cellular hepato-toxicity models compared to a clinical compound BMS-986020 which has been withdrawn. We propose to profile the two LPAR1 antagonists for utility in PBC for their ability to modulate key inflammatory signaling molecules IFNγ and IL-17 and itch responses in pre-clinical models. Completion of lead profiling will result in selection of a single lead that will be evaluated in a pre-clinical model of PBC, conducted at University of California Davis. These studies will determine the feasibility of developing a LPAR1 antagonist for treatment of PBC.