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）：在出生之前，肝脏/母亲需要许多功能。因此，在生命的头几个月中，先天性或遗传性肝病的多元将出现。这些疾病中的绝大多数是胆汁疾病，其中未能使肝脏胆汁散落到肠道中。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庭肝内胆汁淤积（PFIC）。当前申请人对PFIC和相关疾病的遗传基础的理解和相关疾病的理解取得了重大进展。但是，我们知道，这些患者中有三分之一至一半保持没有精确的遗传诊断。这部分是由于当前使用的诊断途径的限制，这些诊断途径也昂贵且冗长。但是，这是由于我们尚未发现所有因果基因的程度。在此提案中，我们将NIH资助的儿童肝病研究和教育网络（儿童），Bull博士实验室和欧洲2个最大的儿科肝脏中心的样本资源汇总在一起。通过将这些样本资源和我们在该领域的经验结合在一起，以及遗传技术的最新进步，我们准备实现此处概述的目标。在当前研究的特定目的1中，我们将通过设计和实施具有成本效益，全面的综合筛选来显着改善遗传诊断方法，以在已知的胆汁淤积基因中突变（即以胆汁淤积的形式突变的基因）。这样一来，我们将在已知基因中定义一群没有突变的患者，因此适合纳入针对新基因发现的研究。在特定的目标2中，我们将使用两种强大的技术鉴定新型的胆汁淤积基因。首先，与密切相关父母的孩子的DNA将在SNP（单核苷酸多态性）阵列以及所鉴定的纯合性区域进行基因分型，以绘制含有疾病基因的遗传区域；然后将在患者中测序有希望的候选基因。其次，在选定的患者中，所有已知基因将进行测序。这种方法称为“全外观测序”，非常有效且具有成本效益。将分析外显子组序列以鉴定候选疾病突变，并在较大的患者组中确认结果。从研究的基因发现成分中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这些疾病涉及的新基因，这将不可避免地阐明基本生理学，并导致稳健，快速且负担得起的诊断测试的发展。这些目标既是儿童肝病研究和教育网络（儿童）的战略，以及国家糖尿病和消化研究所和肾脏疾病（NIDDK）的使命，正如其肝病行动计划中所指出的那样。