Advancing our Understanding of Rare Pediatric Liver Diseases

增进我们对罕见小儿肝病的了解

基本信息

批准号：
10640935
负责人：
Kathleen Mary Loomes
金额：
$ 45.1万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10640935
关键词：
Acceleration Address Adherence Aftercare Alagille Syndrome Ancillary Study Bile Acids Biliary Bilirubin Biological Markers Biological Specimen Banks Candidate Disease Gene Caring Cessation of life Child Childhood Cholestasis Clinical Trials Collaborations Cross-Over Studies Databases Development Diagnosis Disease Disease Progression Double-Blind Method Ensure Functional disorder Future Genomics Human Resources Individual Infrastructure Inherited Intervention Studies Investigation Knowledge Life Liver diseases Manuscripts Measures Medical Modeling Natural History Nature Observational Study Operative Surgical Procedures Outcome Outcome Measure Participant Pathogenesis Patients Pediatric Hospitals Performance Pharmaceutical Preparations Phase Philadelphia Placebo Control Placebos Population Procedures Productivity Protein Analysis Proteins Protocols documentation Pruritus Quality of life Randomized Rare Diseases Refractory Request for Applications Research Resources Role Safety Schools Sertraline Sleep Sleep disturbances Tissue Microarray Translational Research Validation Work Xanthomas Zebrafish actigraphy autosome bile duct biobank biomarker discovery body system candidate validation clinical database collaborative approach efficacy evaluation experience high throughput analysis improved improved outcome liver transplantation member open label optimal treatments pediatric patients placebo controlled trial primary outcome recruit response translational study treatment strategy

项目摘要

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.

项目概要该提案是为了回应申请“ChiLDReN”、“童年”延续的请求肝病研究网络。十五年来，经过大家的共同努力，八种胆汁淤积性儿科疾病已得到进展，我们已经建立了一个强大的数据库生物样本库用于进一步研究。关于发病机制、自然史和最佳选择知之甚少。 ChiLDReN 研究的罕见儿童肝脏疾病的治疗策略。我们在儿童之家费城医院 (CHOP) 建议继续参与该联盟，从而推进通过合作研究领域。只有协作才能提高质量和效率向所有被诊断患有该网络研究的疾病之一的个人提供的护理。过去 15 年来，CHOP 一直是 ChiLDReN 中高效的成员。在这个应用程序中，我们建议继续参与ChiLDReN联盟的各个方面，包括临床试验，观察性和介入性研究方案、基因组学举措、研究成果的传播和辅助研究。此外，我们还提出了验证候选基因和蛋白质的提案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）我们建议开发用于蛋白质定位高通量分析的对照和疾病特异性组织微阵列 (TMA)； 2）我们建议研究斑马鱼模型中候选基因的功能。 Alagille 综合征 (ALGS) 是一种常染色体显性遗传疾病，其特征是胆管缺乏和胆汁淤积以及其他器官系统的表现。许多 ALGS 患者患有严重的胆汁淤积，胆红素和胆汁酸显着升高，出现黄色瘤和严重瘙痒对生活质量影响重大。尽管瘙痒症对日常生活的许多方面都有影响，包括学校和睡眠在内，有效的医疗疗法很少。继续经历的患者尽管使用所有可用疗法进行治疗，但顽固性瘙痒可能需要手术干预，例如胆道改道，甚至在最难治性病例中进行肝移植。因此，有一个关键的未满足需要安全有效的药物疗法来治疗 ALGS 和其他疾病中的胆汁淤积、瘙痒症。我们提议进行舍曲林治疗瘙痒的随机、双盲交叉研究阿拉吉尔综合症。结果测量将评估瘙痒、睡眠、生活质量和自分泌运动因子的变化使用活性药物或安慰剂治疗后的活动。还将评估安全性和耐受性。成功的这项研究的完成将确定舍曲林治疗 ALGS 和瘙痒症的疗效潜在地确定可用作该人群客观研究终点的睡眠变量。我们预计这项工作将贡献有关治疗瘙痒的新知识胆汁淤积患者。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Notch signaling in human development and disease.

DOI：
10.1016/j.semcdb.2012.01.010
发表时间：
2012-06
期刊：
SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY
影响因子：
7.3
作者：
Penton, Andrea L.;Leonard, Laura D.;Spinner, Nancy B.
通讯作者：
Spinner, Nancy B.

Evidence from human and zebrafish that GPC1 is a biliary atresia susceptibility gene.

DOI：
10.1053/j.gastro.2013.01.022
发表时间：
2013-05
期刊：
Gastroenterology
影响因子：
29.4
作者：
Cui S;Leyva-Vega M;Tsai EA;EauClaire SF;Glessner JT;Hakonarson H;Devoto M;Haber BA;Spinner NB;Matthews RP
通讯作者：
Matthews RP

THBS2 Is a Candidate Modifier of Liver Disease Severity in Alagille Syndrome.

DOI：
10.1016/j.jcmgh.2016.05.013
发表时间：
2016-09
期刊：
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
影响因子：
7.2
作者：
Tsai, Ellen A;Gilbert, Melissa A;Grochowski, Christopher M;Underkoffler, Lara A;Meng, He;Zhang, Xiaojie;Wang, Michael M;Shitaye, Hailu;Hankenson, Kurt D;Piccoli, David;Lin, Henry;Kamath, Binita M;Devoto, Marcella;Spinner, Nancy B;Loomes, Kathleen M
通讯作者：
Loomes, Kathleen M

Jagged1 (JAG1): Structure, expression, and disease associations.