The Childhood Liver Disease Research and Education Network (ChiLDREN)

儿童肝病研究和教育网络 (ChiLDREN)

• 批准号: 9552412
• 负责人: SAUL J. KARPEN
• 金额: $ 43.37万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-07 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9552412
• 关键词: 2 year old; 4 year old; Achievement; African American; Age; Agonist; Ancillary Study; Biliary Atresia; Bioinformatics; Biological Markers; Cardiac; Caring; Cessation of life; Child; Childhood; Cholestasis; Clinical; Clinical Data; Clinical Research; Code; DNA; DNA Sequencing Facility; Data; Data Set; Databases; Defect; Development; Disease; Disease Progression; Education; Enrollment; Etiology; Funding; Future; Genes; Genetic; Genetic Determinism; Genome; Genomics; Goals; Grant; Handedness; Healthcare; Human Resources; Individual; Infant; Investigation; Laboratories; Lead; Life; Liver; Liver diseases; Locales; Logic; Measures; Medical; Modeling; Outcome; Parents; Participant; Patient-Focused Outcomes; Patients; Phenotype; Population; Portal Hypertension; Provider; Research; Research Infrastructure; Risk; Sequence Analysis; Site; Situs Inversus; Southeastern United States; Structural defect; Therapeutic; Therapeutic Intervention; Thrombocytopenia; TimeLine; Transplantation; Variant; With laterality; base; cohort; exome; exome sequencing; expectation; experience; genetic makeup; genetic variant; improved; indexing; individual patient; innovation; member; new therapeutic target; novel; outcome prediction; patient stratification; public health relevance; response; success; verification and validation

DESCRIPTION (provided by applicant): The overarching aims of this Center are to help advance the clinical, research, and educational goals of the ChiLDREN grant with a particular emphasis on engaging cutting-edge genome studies as a basis for discovery, innovation, and improvements in outcomes and care. As such, the aims of this application are not only to provide comprehensive research opportunities for all children who fit enrollment criteria for ChiLDREN throughout the Southeastern US. We are also planning to embark upon 3 genomically-centered Research Aims: Aim 1: Explore the genetic determinants of outcomes in biliary atresia (BA). We hypothesize that by detailed, broad-based, unbiased exploration of individual patient genomic determinants (e.g., whole exome sequencing), we will be able to assign genetic categorization of children into those able to adapt well post-Hepatoportoenterostomy (HPE), and those who do not. Intial findings have identified variants in a pathophysiologically-relevant gene that associate with poor outcome after HPE. Aim 2: Determine causes of BA with Laterality Defects. This will proceed by identifying carefully-phenotyped individuals with biliary atresia with laterality defects. To date, 20 trios have been exome sequenced, and analyses are ongoing, with expectations to validate such findings in the larger, BA cohort in ChiLDREN. Aim 3: Explore GGT as a marker for development and progression of portal hypertension in BA subjects with native livers over the age of 2. Preliminary data support the concept that an elevated GGT at age 2 predicts the development of portal hypertension indices and we will utilize the ChiLDREN database to validate and fine- tune these findings, with the goal being to develop GGT as a biomarker of disease progression in BA. The latter will have relevance for a planned study of a novel FXR agonist in these older BA patients in this consortium. The final proposal is to make a single-site exome sequencing and bioinformatics locale within the Emory Genetics Lab under the guidance of Dr. Madhuri Hegde, with close interweaving of longitudinal information from the DCC to develop models, stratify patients, and predict outcomes. Taken together, the focus upon exome sequencing in this population of diseases that manifest early in life and can be stratified into readily-identifible outcome groups, are arguably the ideal group of patients ever collected to deliver etiologic and therapeutic discoveries in cholestasis. For these serious pediatric liver diseases, none with effective medical therapies, studies like these will not only benefit this population, but are likey to provide a deep understanding of the mechanisms underlying liver disease progression in patients of all ages.

描述（由申请人提供）：该中心的总体目的是帮助促进儿童授予的临床，研究和教育目标，特别着重于吸引尖端的基因组研究，以此作为发现，创新以及成果和护理改善的基础。因此，本申请的目的不仅是为所有适合美国东南部儿童入学标准的儿童提供全面的研究机会。我们还计划踏上3个以基因组为中心的研究目的：目标1：探索胆道闭锁（BA）结果的遗传决定因素。我们假设，通过对个体患者基因组决定因素（例如，整个外显子组测序）的详细，基于广泛的，公正的探索，我们将能够将儿童的遗传分类分配到能够适应良好后血管造口术后术后良好后的遗传分类（HPE），以及那些没有的人。 Intial发现已经确定了与HPE后结果相关的病理生理学基因中的变体。 AIM 2：确定具有横向缺陷的BA原因。这将通过识别精心型型胆道闭锁的人的侧向缺陷。迄今为止，已经测序了20个三重奏，并且正在进行分析，期望在儿童中验证较大的BA队列中的此类发现。 AIM 3：探索GGT作为2岁以上本地肝脏的门户高血压发展和进展的标志。初步数据支持这样一个概念，即2岁时的GGT升高可以预测门户高血压指数的发展，我们将利用儿童数据库来验证和良好的疾病，以这些疾病的疾病发展，以发展为BA，以此为BA，以此为ba。后者将与该财团这些老年BA患者的新型FXR激动剂的计划研究相关。最终的建议是在Madhuri Hegde博士的指导下在Emory遗传学实验室内进行单个位点外显子组测序和生物信息学位置，并密切从DCC的纵向信息交织以开发模型，分层患者并预测癌症。综上所述，在这种疾病人群中的外显子组测序的重点可以说是有史以来在胆汁淤积中提供病因学和治疗性发现的理想患者。对于这些严重的小儿肝脏疾病，没有有效的医疗疗法，此类研究不仅会使该人群受益，而且会对所有年龄段患者的肝脏疾病进展的机制有深刻的了解。