Advancing our Understanding of Rare Pediatric Liver Diseases

项目摘要 这一建议是为了回应申请延续儿童，儿童 肝病研究网络。在过去的15年里，通过协调努力， 八种胆汁淤积性儿科疾病已经进展，我们已经建立了一个强大的数据库， 用于进一步研究的生物储存库。关于其发病机制、自然史和最佳治疗方法知之甚少。 ChiLDReN研究的罕见儿科肝病的治疗策略。我们在儿童之家 费城医院（CHOP）建议继续参与该联盟，从而推动 通过合作研究。只有通过协作，才能提质增效 向所有被诊断患有该网络所研究的疾病之一的个人提供护理。 在过去的15年里，CHOP一直是ChiLDReN的高产成员。在本申请中，我们 建议继续参与ChiLDReN联盟的各个方面，包括临床试验， 观察性和干预性研究方案、基因组学倡议、研究结果的传播， 辅助研究。此外，我们还提出了验证候选基因和蛋白质的建议 通过网络基因组学和生物标志物研究通过两个目标确定。1)我们建议发展 用于蛋白质定位的高通量分析的对照和疾病特异性组织微阵列（TMA）; 2） 我们建议在斑马鱼模型中研究候选基因的功能。 Alagille综合征（ALGS）是一种常染色体显性遗传疾病，其特征是胆管缺乏， 胆汁淤积沿着其他器官系统的表现。许多ALGS患者有严重的胆汁淤积， 胆红素和胆汁酸显著升高，出现黄色瘤和严重瘙痒， 对生活质量的重大影响。尽管瘙痒症对日常生活的许多方面有使人衰弱的影响， 包括上学和睡眠，几乎没有有效的医学疗法。患者继续经历 尽管使用所有可用的疗法进行治疗，但顽固性瘙痒可能需要手术干预， 胆道分流术，甚至在最难治的情况下进行肝移植。因此，有一个关键的未满足的 需要安全有效的药物治疗ALGS和其他疾病中的胆汁淤积性瘙痒症。我们 拟进行一项舍曲林治疗瘙痒症的随机、双盲、交叉研究， Alagille综合征结果指标将评估瘙痒、睡眠、生活质量和自分泌运动因子的变化 活性药物或安慰剂治疗后的活性。还将评估安全性和耐受性。成功 本研究的完成将确定舍曲林作为治疗ALGS瘙痒症的有效性， 潜在地确定可用作该人群中的客观研究终点的睡眠变量。我们 预期这项工作将有助于新的知识，关于治疗瘙痒症， 胆汁淤积患者。

PROJECT SUMMARY This proposal is in response to a request for applications for the Continuation of ChiLDReN, the Childhood Liver Disease Research Network. Over the past fifteen years, through a coordinated effort, investigations of eight cholestatic pediatric disorders have been advanced and we have established a robust database and biorepository for further research. Little is known about the pathogenesis, natural history, and optimal treatment strategies for the rare pediatric liver diseases investigated by ChiLDReN. We at The Children's Hospital of Philadelphia (CHOP) propose to continue to participate in this Consortium, and thereby advance the field through collaborative research. Only through collaboration can we improve the quality and efficiency of care provided to all individuals diagnosed with one of the diseases studied by this network. CHOP has been a highly productive member of ChiLDReN for the last 15 years. In this application, we propose to continue our participation in all aspects of the ChiLDReN consortium, including clinical trials, observational and interventional study protocols, genomics initiatives, dissemination of research findings and ancillary studies. In addition, we have included a proposal for validation of candidate genes and proteins identified through Network Genomics and Biomarker studies through two Aims. 1) We propose to develop control and disease-specific tissue microarrays (TMA) for high throughput analysis of protein localization; 2) We propose to investigate the function of candidate genes in a zebrafish model. Alagille syndrome (ALGS) is an autosomal dominant disorder characterized by bile duct paucity and cholestasis along with manifestations in other organ systems. Many ALGS patients have profound cholestasis, with significantly elevated bilirubin and bile acids, development of xanthomas and severe pruritus that has a major impact on quality of life. Despite the debilitating effects of pruritus on many aspects of daily life, including school and sleep, there are few effective medical therapies. Patients who continue to experience intractable pruritus despite treatment with all available therapies may require surgical intervention such as biliary diversion, or even liver transplantation in the most refractory cases. Therefore, there is a critical unmet need for safe and effective medical therapies for the cholestasis of pruritus in ALGS and other disorders. We propose to conduct a randomized, double-blind crossover study of sertraline for the treatment of pruritus in Alagille syndrome. Outcome measures will assess changes in pruritus, sleep, quality of life and autotaxin activity after treatment with active drug or placebo. Safety and tolerability will also be assessed. Successful completion of this study will determine the efficacy of sertraline as a therapy for pruritus in ALGS and potentially identify sleep variables that could be used as objective study endpoints in this population. We anticipate that this work will contribute new knowledge regarding the treatment of pruritus in cholestatic patients.