New genes and pathomechanisms of congenital abnormalities of the kidney (CAKUT)
先天性肾脏异常(CAKUT)的新基因和病理机制
基本信息
- 批准号:8507725
- 负责人:
- 金额:$ 34.69万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-07-05 至 2015-02-28
- 项目状态:已结题
- 来源:
- 关键词:AccountingAnimal ModelBiological ModelsCandidate Disease GeneChildChronic Kidney FailureClinical DataCongenital AbnormalityConsensusDNADataDatabasesDiagnosticDialysis procedureDiseaseExonsFamilyGene MutationGenesGenomeGenomicsHealthHumanKidneyKidney TransplantationLarge-Scale SequencingLeadMapsMethodsModelingMolecular GeneticsMutationPhysiologicalPreclinical Drug EvaluationProphylactic treatmentRecruitment ActivityRoleShippingShipsSingle-Gene DefectTestingUrinary tractZebrafishanimal model developmentcohortexomemouse modelnew technologynovelnovel strategiespositional cloningpublic health relevancezebrafish development
项目摘要
DESCRIPTION (provided by applicant): New genes and pathomechanisms of congenital abnormalities of the kidney (CAKUT). Chronic kidney diseases (CKD) take one of the highest tolls on human health, requiring dialysis or kidney transplantation for survival. Congenital abnormalities of the kidney and urinary tract (CAKUT) constitute the most frequent cause of CKD in children, accounting for ~50% of all cases. We identified previously, by positional cloning, 2 novel dominant single-gene causes of CAKUT (Ruf PNAS 101:890, 2004; Hoskins AJHG 80:800, 2007). We, now, recruited genomic DNA and clinical data in a multi-ethnic cohort of children with CAKUT from 456 different families, and generated preliminary data by total genome homozygosity mapping that demonstrate the presence of recessive single-gene loci in sib ships and single cases with non-syndromic CAKUT. We also established a new technology of exome capture with consecutive large-scale sequencing for the identification of novel single-gene causes of CAKUT. In 20 sib ships we mapped 1 new locus and several putative loci, which are homozygous by descent, as strong candidate loci for causative recessive mutations in unidentified genes. From these data and from animal models of CAKUT we hypothesize that single-gene mutations in many distinct unidentified genes, both recessive and dominant, will represent novel causes of CAKUT. We will now employ our newly established method of homozygosity mapping with exon capture and consecutive large- scale sequencing to identify and functionally characterize novel CAKUT-causing genes. We will pursue the following aims: 1. Identify novel recessive causes of CAKUT by homozygosity mapping, exon capture, and large-scale (LS) sequencing in families with homozygosity by descent. 2. Identify novel dominant causes of CAKUT by 2.1M Whole Human Exome Capture and LS sequencing. 3. Functionally characterize the newly identified CAKUT genes in zebrafish models.
PUBLIC HEALTH RELEVANCE: Congenital abnormalities of the kidney and urinary tract (CAKUT) account for about ~50% of chronic kidney disease in children. No prophylaxis or curative treatment is available. Although many forms of CAKUT are very likely caused by single-gene defects, only few causative genes have been identified so far. We recently established a new approach of homozygosity mapping, exon capture and large-scale sequencing for identification of new CAKUT-causing genes. We will apply these new approaches to a worldwide cohort of 456 families with CAKUT, which we have recruited. The identification of new single-gene causes of SRNS will: i) lead to identification of novel single-genes causes of CAKUT; ii) introduce the new technologies of exon capture and large-scale sequencing into the diagnostics of CAKUT; iii) permit early, unequivocal molecular genetic diagnostics; iv) help unravel the disease mechanisms of CAKUT; v) allow detailed mechanistic studies of the pathomechanisms of CAKUT in zebrafish models; vi) permit development of zebrafish model systems for high-throughput drug screening for this disease.
描述(由申请人提供):先天性肾脏异常(CAKUT)的新基因和病理机制。慢性肾脏疾病(CKD)是人类健康损失最大的疾病之一,需要透析或肾移植才能生存。先天性肾脏和泌尿道异常(CAKUT)是儿童CKD最常见的原因,约占所有病例的50%。我们先前通过定位克隆鉴定了CAKUT的2种新的显性单基因病因(Ruf PNAS 101:890,2004;霍斯金斯AJHG 80:800,2007)。现在,我们在来自456个不同家庭的CAKUT儿童的多种族队列中招募了基因组DNA和临床数据,并通过全基因组纯合性作图产生了初步数据,这些数据表明在非综合征CAKUT的同胞和单个病例中存在隐性单基因位点。我们还建立了一种新的外显子组捕获技术与连续的大规模测序鉴定CAKUT的新的单基因原因。在20个同胞中,我们绘制了1个新的基因座和几个推定的基因座,这是纯合的血统,作为强有力的候选基因座的原因不明的基因隐性突变。从这些数据和动物模型的CAKUT,我们假设,单基因突变在许多不同的身份不明的基因,隐性和显性,将代表新的原因CAKUT。我们现在将使用我们新建立的纯合性作图方法,外显子捕获和连续大规模测序来鉴定和功能表征新的CAKUT引起基因。我们将追求以下目标:1。通过纯合性定位、外显子捕获和大规模(LS)测序,在具有纯合性血统的家族中识别CAKUT的新隐性病因。2.通过2.1M全人类外显子组捕获和LS测序鉴定CAKUT的新主要原因。3.在斑马鱼模型中对新鉴定的CAKUT基因进行功能表征。
公共卫生相关性:先天性肾脏和泌尿道异常(CAKUT)约占儿童慢性肾脏疾病的50%。没有预防或治愈性治疗。虽然许多形式的CAKUT很可能是由单基因缺陷引起的,但迄今为止只有少数致病基因被确定。我们最近建立了一种新的方法,纯合性定位,外显子捕获和大规模测序鉴定新的CAKUT引起的基因。我们将把这些新方法应用于我们招募的456个CAKUT家庭的全球队列。SRNS的新单基因病因的鉴定将:i)导致CAKUT的新单基因病因的鉴定; ii)将外显子捕获和大规模测序的新技术引入CAKUT的诊断中; iii)允许早期、明确的分子遗传诊断; iv)帮助解开CAKUT的疾病机制; v)允许在斑马鱼模型中对CAKUT的病理机制进行详细的机制研究; vi)允许开发用于针对该疾病的高通量药物筛选的斑马鱼模型系统。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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FRIEDHELM HILDEBRANDT其他文献
FRIEDHELM HILDEBRANDT的其他文献
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{{ truncateString('FRIEDHELM HILDEBRANDT', 18)}}的其他基金
Integrating large scale genomics and functional studies to accelerate FSGS/NS discovery
整合大规模基因组学和功能研究以加速 FSGS/NS 发现
- 批准号:
10047547 - 财政年份:2020
- 资助金额:
$ 34.69万 - 项目类别:
Integrating large scale genomics and functional studies to accelerate FSGS/NS discovery
整合大规模基因组学和功能研究以加速 FSGS/NS 发现
- 批准号:
10441350 - 财政年份:2020
- 资助金额:
$ 34.69万 - 项目类别:
Integrating large scale genomics and functional studies to accelerate FSGS/NS discovery
整合大规模基因组学和功能研究以加速 FSGS/NS 发现
- 批准号:
10237944 - 财政年份:2020
- 资助金额:
$ 34.69万 - 项目类别:
Integrating large scale genomics and functional studies to accelerate FSGS/NS discovery
整合大规模基因组学和功能研究以加速 FSGS/NS 发现
- 批准号:
10652318 - 财政年份:2020
- 资助金额:
$ 34.69万 - 项目类别:
New genes and pathomechanisms of congenital abnormalities of the kidney (CAKUT)
先天性肾脏异常(CAKUT)的新基因和病理机制
- 批准号:
8318885 - 财政年份:2010
- 资助金额:
$ 34.69万 - 项目类别:
New genes and pathomechanisms of congenital abnormalities of the kidney (CAKUT)
先天性肾脏异常(CAKUT)的新基因和病理机制
- 批准号:
8630181 - 财政年份:2010
- 资助金额:
$ 34.69万 - 项目类别:
New genes and pathomechanisms of congenital abnormalities of the kidney (CAKUT)
先天性肾脏异常(CAKUT)的新基因和病理机制
- 批准号:
8105180 - 财政年份:2010
- 资助金额:
$ 34.69万 - 项目类别:
New genes and pathomechanisms of congenital abnormalities of the kidney (CAKUT)
先天性肾脏异常(CAKUT)的新基因和病理机制
- 批准号:
7940309 - 财政年份:2010
- 资助金额:
$ 34.69万 - 项目类别:
Exon capture and large-scale sequencing for disease-cause identification, early d
外显子捕获和大规模测序用于疾病原因识别、早期诊断
- 批准号:
7819207 - 财政年份:2009
- 资助金额:
$ 34.69万 - 项目类别:
Exon capture and large-scale sequencing for disease-cause identification, early d
外显子捕获和大规模测序用于疾病原因识别、早期诊断
- 批准号:
7936906 - 财政年份:2009
- 资助金额:
$ 34.69万 - 项目类别:
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