Advancing our Understanding of Rare Pediatric Liver Diseases

项目总结 这项提议是对《儿童、童年》续展申请的回应。 肝病研究网络。在过去的15年里，通过协调努力，对 8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和 用于进一步研究的生物信息库。对其发病机制、自然病史和最佳发病机制知之甚少。 儿童少见肝病的治疗策略。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 通过合作研究这一领域。只有通过协作，我们才能提高质量和效率 向所有被诊断患有该网络所研究的一种疾病的个人提供的护理。 在过去的15年里，Chop一直是儿童生产力很高的成员。在此应用程序中，我们 提议继续参与儿童联盟的所有方面，包括临床试验， 观察性和干预性研究方案、基因组学倡议、研究成果的传播和 辅助研究。此外，我们还提出了对候选基因和蛋白质进行验证的建议 通过网络基因组学和Biomarker研究确定了两个目标。1)我们建议发展 用于高通量蛋白质定位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病，其特征是胆管缺乏和 胆汁淤积伴随其他器官系统的表现。许多ALGS患者有严重的胆汁淤积， 随着胆红素和胆汁酸的显著升高，黄色瘤的发展和严重的瘙痒 对生活质量有重大影响。尽管瘙痒对日常生活的许多方面都有令人衰弱的影响， 包括上学和睡眠在内，几乎没有有效的医学疗法。继续经历的患者 顽固性瘙痒，尽管使用了所有可用的治疗方法，但可能需要手术干预，例如 胆道分流，甚至在最难治的病例中进行肝移植。因此，有一个关键的未满足 对于ALGS和其他疾病中的瘙痒胆汁淤积症，需要安全和有效的药物治疗。我们 建议进行舍曲林治疗皮肤瘙痒的随机双盲交叉研究 阿拉格尔综合征。结果测量将评估瘙痒、睡眠、生活质量和自体分类的变化 使用活性药物或安慰剂治疗后的活动。安全性和耐受性也将进行评估。成功 这项研究的完成将确定舍曲林作为ALGS和ALGS患者瘙痒的治疗效果 潜在地确定可用作该人群的客观研究终点的睡眠变量。我们 预计这项工作将为治疗皮肤瘙痒提供新的知识。 胆汁淤积症患者。

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.