CHOLESTATIC LIVER DISEASE CONSORTIUM LONGITUDINAL STUDY

胆汁淤积性肝病联盟纵向研究

• 批准号: 7950664
• 负责人: SAUL J. KARPEN
• 金额: $ 0.09万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7950664
• 关键词: Affect; Alagille Syndrome; Ancillary Study; Bile Acid Biosynthesis Pathway; Biological Markers; Body Composition; Bone Density; Breeding; Characteristics; Child; Childhood; Cholestasis; Clinical Research; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; DNA; Data Element; Defect; Disease; Disease Progression; Etiology; Family; Frequencies; Functional disorder; Funding; Future; Genes; Genetic; Genotype; Grant; Growth; Incidence; Individual; Institution; Intervention; Intrahepatic Cholestasis; Liver; Liver diseases; Longitudinal Studies; Natural History; Observational Study; Outcome; Outcome Measure; Participant; Patients; Phenotype; Progressive intrahepatic cholestasis; Rare Diseases; Recording of previous events; Research; Research Personnel; Resources; Sample Size; Sampling; Serum; Severities; Source; Specimen; Therapeutic Intervention; Tissues; United States National Institutes of Health; Urine; alpha 1-Antitrypsin Deficiency; biobank; clinical phenotype; disease phenotype; disorder control; emerging adult; improved; intrahepatic; longitudinal database; repository

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This longitudinal observational study will investigate the nat\plain\f3\fs18 ural history and progression of four genetic causes of intrahepatic cholestasis of childhood, including alpha-1 antitrypsin deficiency (\'e11-AT), Alagille syndrome (AGS), progressive familial intrahepatic cholestasis (PFIC), and bile acid synthesis defects (\plain\f3\fs18 BAD). This study will be conducted as part of the Cholestatic Liver Disease Consortium (CLiC), an NIH-funded multi-centered Rare Disease Clinical Research Consortium. In this study, we will collect defined data elements in a uniform fashion at fixed intervals for five years over a relatively large number of patients with these rare disorders. In addition, a biobank of patient specimens and DNA samples will be established for use in ancillary studies to be performed in addition to this study. By comparing outcome measures between the four liver diseases (i.e., using each disorder as a disease-control for the other disorders), the full impact of each disorder can best be determined in comparison to the other liver diseases. Using the longitudinal database in this fashion, this study will provide an improved understanding of the effects of the cholestatic liver during childhood irrespective of the underlying etiology as well as to the pathophysiology, outcome, and complications of each of the disorders. This initial characterization will allow calculation of sample sizes for future therapeutic intervention clinical trials and provide the baseline to which interventions should be compared. HYPOTHESIS 1. Each of the four intrahepatic cholestatic diseases will have unique phenotypic features and a characteristic natural history. 2. Genotypic differences in participants with each of the cholestatic diseases may influence the disease phenotype and progression. 3. Poor growth and decreased bone mineral density in patients with cholestatic liver diseases is variably dependent on the degree of cholestasis, body composition, and/or the severity of liver synthetic dysfunction. 4. Early biomarkers will be predictive of outcome in cholestatic liver diseases. To determine the clinical phenotype and natural history of each of the four liver diseases during childhood and early adulthood. Specific Aim 2: To determine the frequency of poor growth and decreased bone mineral density and its predictors in all four diseases. Specific Aim 3: To develop a repository of serum, urine, tissue, and DNA specimens, that will be used in future ancillary studies to determine circulating biomarkers that predict disease progression and outcomes, and to identify modifier genes that influence the incidence, severity and progression of liver disease among genetically affected individuals. Specific Aim 4: To determine genotype-phenotype relationships in Alagille syndrome and progressive familial intrahepatic cholestasis (PFIC) disorders. Specific Aim 5: To determine if the natural history and progression of liver disease in alpha-1 antitrypsin deficiency is consistent in a given family with multiply affected children ("breeds true")

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 这项纵向观察研究将调查儿童期肝内胆汁淤积的四种遗传原因的自然病史和进展，包括 α-1 抗胰蛋白酶缺乏症 (\'e11-AT)、Alagille 综合征 (AGS)、进行性家族性胆汁淤积症。肝内胆汁淤积（PFIC）和胆汁酸合成缺陷（\plain\f3\fs18 BAD）。这项研究将作为胆汁淤积性肝病联盟 (CLiC) 的一部分进行，该联盟是一个由 NIH 资助的多中心罕见病临床研究联盟。在这项研究中，我们将以统一的方式在五年内以固定的时间间隔收集相对大量患有这些罕见疾病的患者的定义数据元素。 此外，还将建立患者标本和 DNA 样本的生物库，用于除本研究之外的辅助研究。 通过比较四种肝脏疾病之间的结果测量（即，使用每种疾病作为其他疾病的疾病控制），可以通过与其他肝脏疾病的比较来最好地确定每种疾病的全面影响。 通过以这种方式使用纵向数据库，本研究将更好地了解儿童期胆汁淤积性肝的影响，无论其潜在病因以及每种疾病的病理生理学、结果和并发症如何。 这一初步特征将允许计算未来治疗干预临床试验的样本量，并提供干预措施比较的基线。 假设 1. 四种肝内胆汁淤积性疾病中的每一种都具有独特的表型特征和特有的自然史。 2. 患有每种胆汁淤积性疾病的参与者的基因型差异可能会影响疾病的表型和进展。 3. 胆汁淤积性肝病患者的生长不良和骨密度下降在不同程度上取决于胆汁淤积的程度、身体成分和/或肝合成功能障碍的严重程度。 4. 早期生物标志物将预测胆汁淤积性肝病的结果。 确定四种肝脏疾病在儿童期和成年早期的临床表型和自然史。 具体目标 2：确定所有四种疾病中生长不良和骨矿物质密度降低的频率及其预测因素。 具体目标 3：开发血清、尿液、组织和 DNA 样本库，用于未来的辅助研究，以确定预测疾病进展和结果的循环生物标志物，并识别影响发病率、严重程度和结果的修饰基因。受遗传影响的个体中肝病的进展。 具体目标 4：确定 Alagille 综合征和进行性家族性肝内胆汁淤积 (PFIC) 疾病的基因型-表型关系。 具体目标 5：确定 α-1 抗胰蛋白酶缺乏症导致的肝脏疾病的自然病程和进展在患有多种受影响儿童的特定家庭中是否一致（“繁殖真实”）