Genomics of mammalian posterior urethral valves

哺乳动物后尿道瓣膜的基因组学

基本信息

批准号：
9427411
负责人：
Simone Sanna-Cherchi
金额：
$ 60.61万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-22 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9427411
关键词：
Affect Alleles Apoptosis Architecture Biological Assay Candidate Disease Gene Child Child Care Childhood Clinical Complex Coupled DNA Microarray Chip DNA Resequencing Data Data Set Defect Development Diagnosis Diagnostic Dialysis procedure Disease Disease model Duct (organ) structure Embryo End stage renal failure Epidemiology Etiology Failure Generations Genes Genetic Genetic Heterogeneity Genetic Models Genetic Predisposition to Disease Genomics Genotype Human Human Genetics Hypospadias Link Lower urinary tract Middle Lobe Syndrome Modeling Molecular Morbidity - disease rate Morphogenesis Mus Mutant Strains Mice Mutate Mutation Nucleotides Obstruction Parents Pathogenicity Pathway interactions Patients Phenotype Pilot Projects Play Point Mutation Role SNP genotyping Severity of illness Structure of paramesonephric duct Susceptibility Gene Syndrome Testing Therapeutic Therapeutic Intervention Tissues Transcript Transplantation Urethra Urology Variant Vas deferens structure Work base cohort cost cost effective data modeling design dosage exome exome sequencing fitness gene discovery genetic variant improved insight male malformation mortality mouse model mutant novel personalized care pressure rare variant segregation transcription factor transcriptome transcriptome sequencing transcriptomics validation studies

项目摘要

Posterior urethral valves (PUV) are the major cause of lower urinary tract obstruction in male children and account for 17% of pediatric end-stage renal disease. Despite the severity of the disease and its impact on mortality and morbidity, the molecular basis of this condition is largely unknown, resulting in suboptimal diagnostic and therapeutic strategies. The epidemiology of the disease, characterized by high selective pressure versus a phenotype with low fitness, suggests that dominant de novo mutations or recessive inheritance play a major role in disease determination. This proposal represents the natural continuation of a Pilot project from our O'Brien Center of Urology and aims at the identification of the genetic susceptibility factors for posterior urethral valves (PUV). Our central hypothesis is that rare variants with large effect size on the phenotype underlie the genetic architecture of PUV, and that combining high-throughput genomic studies with analysis of two mouse models of disease will lead to the identification of novel disease genes. Our preliminary data using exome and geneome sequencing, CNV analysis, and functional modeling in vertebrate strongly indicate that we can successfully identify novel genomic variants with large effect size, even in scenario of complex genetic architecture and high genetic heterogeneity. In particular, by studying CNVs in a large cohort of PUV patient, we identified different novel candidate genes for PUV and lower urinary tract malformation. We next demonstrated that mouse transcript dosage of one of these gene candidates, Tbx6, results in highly penetrant maldevelopment and lack of canalization of urethra similar to human PUV. Simultaneously, we have identified a set of genes that are disregulated in mouse mutants lacking Sall1, a transcription factor that when mutated in humans causes Townes-Brocks Syndrome (TBS), a clinical entity characterized by different malformations, including anorectal defects, PUV, and hypospadias. We now propose to extend our sequencing effort to additional 200 PUV trios, and to replicate findings in a large cohort of patients to identify novel genes. We will also characterize the lower urinary tract defects of Sall1 and Tbx6 and generate whole transcriptome datasets to identify downstream targets and facilitate gene identification in humans. This study is designed to solve the molecular etiology of PUV, to improve diagnosis and individualized care for children affected by this severe condition, and to identify pathways that can be amenable to therapeutic interventions.

后尿道瓣（PUV）是男性儿童尿路阻塞较低的主要原因，占小儿终末期肾脏疾病的17％。尽管疾病严重及其对死亡率和发病率，这种情况的分子基础在很大程度上未知，导致次优诊断和治疗策略。该疾病的流行病学以高选择性为特征压力与低健身的表型表明，从头突变或隐性继承在疾病确定中起主要作用。该提案代表了我们奥布莱恩泌尿外科中心的试点项目的自然延续旨在鉴定后尿道瓣膜（PUV）的遗传敏感性因子。我们的中心假设是，对表型的影响很大的稀有变体是遗传结构的基础 PUV，以及将高通量基因组研究与两种小鼠疾病模型的分析相结合的导致鉴定新型疾病基因。我们使用外显子和基因组测序的初步数据， CNV分析和脊椎动物中的功能建模强烈表明我们可以成功识别新颖即使在复杂的遗传结构和高遗传的情况下，具有较大效果大小的基因组变体也很大异质性。特别是，通过研究大量PUV患者中的CNV，我们确定了不同的新颖新颖 PUV和较低尿路畸形的候选基因。接下来，我们证明了鼠标成绩单这些基因候选物之一TBX6的剂量导致高度渗透性的Maldevelverment和缺乏类似于人类PUV的尿道的管道化。同时，我们确定了一组基因在缺乏SALL1的小鼠突变体中没有调节，这是一种转录因子，当在人类中突变时 Townes-Brocks综合征（TBS），一个以不同畸形为特征的临床实体，包括厌食症缺陷，PUV和Hypospadias。现在，我们建议将我们的测序工作扩展到其他200个PUV三重奏，并在大量患者中复制发现以鉴定新基因。我们还将描述下部 SALL1和TBX6的尿路缺陷并生成整个转录组数据集以识别下游靶标并促进人类的基因鉴定。这项研究旨在解决分子病因 PUV，以改善受这种严重状况影响的儿童的诊断和个性化护理，并确定可以接受治疗干预措施的途径。