The Genetic Basis of Pediatric Cholestasis

小儿胆汁淤积的遗传基础

基本信息

批准号：
8545514
负责人：
LAURA N BULL
金额：
$ 56.81万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-24 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8545514
关键词：
Adult Alleles Amish Benign recurrent intrahepatic cholestasis Bile fluid Biological Assay Birth Candidate Disease Gene Child Childhood Cholestasis Chromosome Mapping Code Collection Complex Country Custom DNA Data Development Diabetes Mellitus Diagnosis Diagnostic Diagnostic Procedure Diagnostic tests Digestive System Disorders Disease Disease Management Education Europe Exons Failure Family Functional RNA Funding Gene Mutation Genes Genetic Genetic Predisposition to Disease Genetic Techniques Genome Genotype Goals Health Hereditary Disease Hospitals Impairment Inherited Institutes Intestines Investigation Kidney Diseases Knowledge Laboratories Lead Life Light Liver Liver diseases London Maps Methodology Mission Mothers Mutate Mutation National Institute of Diabetes and Digestive and Kidney Diseases Nucleic Acid Regulatory Sequences Parents Pathway interactions Patients Performance Phenotype Physiology Placenta Poland Progressive intrahepatic cholestasis Publishing RNA Splicing Reporting Research Resources Sampling Screening procedure Single Nucleotide Polymorphism Techniques Transplantation United States National Institutes of Health Variant base cohort college cost effective design exome experience gene discovery genetic technology improved liver transplantation next generation novel tool

项目摘要

DESCRIPTION (provided by applicant): Before birth many functions required of the liver can be replaced by the placenta/mother. It is therefore in the first few months of life that the majoriy of congenital or genetic liver disease will present. The great majority of these diseases are cholestatic diseases, in which there is failure to make, or drain, bile from the liver into the intestine. A clinically defined group of patients was identified some years ago, and their disorder termed progressive familial intrahepatic cholestasis (PFIC). Significant advances in the understanding of the genetic basis of PFIC and related disorders have been made by the current applicants. However, we know that between one third and one half of these patients remain without a precise genetic diagnosis. This is partly due to limitations in the currently employed diagnostic pathways, which are also expensive and lengthy; however, it is due to a greater degree to our not having yet discovered all the causative genes. In this proposal, we bring together sample resources from the NIH-funded Childhood Liver Disease Research and Education Network (ChiLDREN), Dr. Bull's laboratory, and the 2 largest pediatric liver centers in Europe. By combining these sample resources and our experience in the field, with recent dramatic advances in genetic technology, we are poised to achieve the goals outlined here. In Specific Aim 1 of the current study, we will seek to dramatically improve genetic diagnostic approaches, through the design and implementation of cost-effective, comprehensive screens for mutation in known cholestasis genes (i.e. genes mutated in forms of cholestasis). In so doing, we will define a cohort of patients without mutation in known genes, who are therefore suitable for inclusion in studies aimed at new gene discovery. In Specific Aim 2, we will identify novel cholestasis genes using two powerful techniques. Firstly, DNA from children of closely related parents will be genotyped on SNP (single nucleotide polymorphism) arrays, and regions of homozygosity identified, to map genetic regions containing disease genes; promising candidate genes will then be sequenced in patients. Secondly, in selected patients, all known genes will be sequenced. This approach, termed 'whole-exome sequencing,' is remarkably efficient and cost-effective. The exome sequence will be analyzed to identify candidate disease mutations, and results confirmed in a larger patient set. The data gained from the gene discovery components of the study will be used to refine the diagnostic testing pathway in an iterative fashion. The result of our proposed studies will be the identification of new genes involved in these diseases, which will inevitably shed light on basic physiology, and lead to development of robust, rapid and affordable diagnostic testing. These goals are central to both the strategy of the Childhood Liver Disease Research and Education Network (ChiLDREN) and the mission of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), as stated in its Action Plan for Liver Disease Research.

描述（由申请人提供）：出生前，肝脏所需的许多功能可以由胎盘/母亲替代。因此，大多数先天性或遗传性肝病会在生命的最初几个月出现。这些疾病中的绝大多数是胆汁淤积性疾病，即无法将胆汁从肝脏制造或排入肠道。几年前确定了一组临床定义的患者，他们的疾病称为进行性家族性肝内胆汁淤积症（PFIC）。目前的申请人在对 PFIC 和相关疾病的遗传基础的理解方面已经取得了重大进展。然而，我们知道这些患者中有三分之一到一半仍未得到精确的基因诊断。这部分是由于目前使用的诊断途径的局限性，这些途径也昂贵且漫长；然而，这在很大程度上是由于我们还没有发现所有的致病基因。在本提案中，我们汇集了来自 NIH 资助的儿童肝病研究和教育网络 (ChiLDREN)、Bull 博士实验室以及欧洲 2 个最大的儿科肝脏中心的样本资源。通过将这些样本资源和我们在该领域的经验结合起来，再加上遗传技术最近取得的巨大进步，我们准备实现此处概述的目标。在本研究的具体目标 1 中，我们将通过设计和实施具有成本效益的全面筛查已知胆汁淤积基因（即以胆汁淤积形式突变的基因）突变，寻求显着改进遗传诊断方法。在此过程中，我们将定义一组已知基因没有突变的患者，因此适合纳入旨在发现新基因的研究。在具体目标 2 中，我们将使用两种强大的技术来识别新的胆汁淤积基因。首先，对亲缘关系密切的子女的DNA进行SNP（单核苷酸多态性）芯片的基因分型，并鉴定纯合性区域，以绘制含有疾病基因的遗传区域图谱；然后将在患者体内对有希望的候选基因进行测序。其次，在选定的患者中，所有已知的基因都将被测序。这种方法被称为“全外显子组测序”，非常高效且具有成本效益。将分析外显子组序列以确定候选疾病突变，并在更大的患者组中确认结果。从该研究的基因发现部分获得的数据将用于以迭代方式完善诊断测试途径。我们提出的研究的结果将是鉴定与这些疾病有关的新基因，这将不可避免地揭示基础生理学，并导致稳健、快速和负担得起的诊断测试的发展。这些目标是儿童肝病研究和教育网络 (ChiLDREN) 战略的核心，也是国家糖尿病、消化和肾脏疾病研究所 (NIDDK) 使命的核心，正如其肝病研究行动计划所述。