Genetics of Congenital Obstructive Uropathy

先天性梗阻性尿病的遗传学

基本信息

批准号：
8765795
负责人：
Simone Sanna-Cherchi
金额：
$ 44.34万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-12 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8765795
关键词：
Accounting Animal Model Biological Assay Candidate Disease Gene Categories Cell Culture Techniques Childhood Code Communities Computer Simulation DNA Resequencing Data Development Diagnostic Disease Embryonic Development Family Fibroblast Growth Factor Genes Genetic Genetic Crosses Genetic Heterogeneity Genetic Screening Goals Human Hydronephrosis Image Kidney Kidney Failure Knock-out Knockout Mice Modeling Molecular Profiling Mus Mutation Pathogenesis Patients Penetrance Pregnancy Proteins Research Signal Transduction Staging Susceptibility Gene Testing Therapeutic Transgenic Organisms Ultrasonography Urinary tract Variant Zebrafish base cohort congenital anomaly cost data sharing disease-causing mutation exome exome sequencing genetic pedigree innovation insight malformation mouse model nephrogenesis next generation sequencing novel novel diagnostics novel therapeutics overexpression prenatal public health relevance trait urinary tract obstruction

项目摘要

DESCRIPTION (provided by applicant): Congenital Anomalies of the Kidney and the Urinary Tract (CAKUT) account for 40-50% of pediatric end-stage kidney failure worldwide. Among CAKUT categories, congenital obstructive uropathy represents a common and severe form of malformation. Congenital hydronephrosis is the most frequent anomaly of the urinary tract detected by prenatal ultrasound, occurring in up to 2% of normal pregnancies. Congenital obstructive uropathy can occur as familial or sporadic disease with highly variable phenotypic expression. Due to paucity of fundamental insight about primary pathogenesis, diagnostic and therapeutic options are severely limited. We recently implemented whole exome sequencing combined to functional modeling in zebrafish to identify dominant mutations in DSTYK in up to 2.3% of patients with congenital obstructive uropathy and associated urinary tract malformations (Sanna-Cherchi et al, New Engl J Med 2013). The protein encoded by DSTYK acts as a positive regulator of fibroblast growth factor (FGF) signaling during nephrogenesis. This study illustrates the power of combining whole exome sequencing with functional modeling in animal models to identify novel disease causing mutations in traits characterized by high genetic heterogeneity, incomplete penetrance, variable phenotypic expression, and small/medium pedigree size. Here we propose to characterize the function of DSTYK during embryonic development and nephrogenesis in cell cultures and in mouse models harboring Dstyk mutations, to extend our gene identification effort to 50 additional families with autosomal dominant congenital obstructive uropathy and to perform functional modeling in zebrafish to identify novel susceptibility genes. This study will provide insight into the pathogenesis of congenital obstructive uropathy in humans and animal models and will help develop new diagnostic and therapeutic strategies.

描述（由申请人提供）：肾脏和尿路（Cakut）的先天异常，占全球小儿终末期肾脏衰竭的40-50％。在Cakut类别中，先天性阻塞性尿液病是一种常见且严重的畸形形式。先天性肤色是产前超声检测到的尿路最常见的异常，最多发生在正常妊娠的2％中。先天性阻塞性泌尿病可能是家族性或零星疾病，具有高度可变的表型表达。由于缺乏对主要发病机理的基本见解，因此诊断和治疗选择受到严重限制。最近，我们实施了整个外显子组测序与斑马鱼中的功能建模，以鉴定多达2.3％的先天性阻塞性尿炎和相关尿路畸形患者的DSTYK中的显性突变（Sanna-Cherchi等人，New Engl J Med 2013）。 DSTYK编码的蛋白质是肾脏发生过程中成纤维细胞生长因子（FGF）信号的阳性调节剂。这项研究说明了在动物模型中将整个外显子组测序与功能模型相结合的力量，以鉴定新的疾病，导致特征的突变，其特征是高遗传异质性，不完整的渗透率，可变的表型表达和小/中等谱系大小。在这里，我们建议在细胞培养物和具有DSTYK突变的小鼠模型中表征DSTYK在胚胎发育和肾脏发生过程中的功能，以将我们的基因鉴定工作扩展到50个其他具有常染色体显性固定的先天性阻塞性尿症的家族，并在Zebrafish中进行功能模型，以识别新型易感性基因。这项研究将洞悉人类和动物模型中先天性阻塞性尿病的发病机理，并有助于发展新的诊断和治疗策略。