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Genetic and Molecular Etiology of Developmental Kidney and Urinary Tract Abnormalities in the DiGeorge, or 22q11.2, Syndrome.

DiGeorge 或 22q11.2 综合征发育性肾脏和尿路异常的遗传和分子病因学。

基本信息

批准号：
10399743
负责人：
Jeremiah Martino
金额：
$ 0.25万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10399743
关键词：
22q11.2 Ablation Accounting Adaptor Signaling Protein Address Affect Alternative Splicing Animal Model Animals Binding Biochemical Biological Assay CRKL gene Cells Childhood Chromosomes Complex Coupled DNA Sequence Alteration Data Defect Development DiGeorge Syndrome Diagnostic Disease Dysplasia End stage renal failure Etiology Event Exons Family Genes Genetic Genetic Models Goals Human Human Genetics Hydronephrosis Impairment Kidney Kidney Failure Lead Life Light Metanephric Diverticulum Methodology Modeling Molecular Morphogenesis Mus Mutant Strains Mice Mutate Mutation Neurologic Organogenesis Outcome Pathogenesis Pathway interactions Patients Pattern Phenotype Play Point Mutation Pregnancy Prenatal Diagnosis Protein Family Protein Isoforms Proteins RNA Splicing Regulation Role SH3 Domains Signal Transduction Structure Syndrome System Terminator Codon Testing Therapeutic Tissues Transcript Ultrasonography Ureter Urinary tract Variant Vertebrates Work base case control cell type congenital anomaly design developmental genetics differential expression experimental study falls genomic data human disease imaging study in vivo innovation insight interdisciplinary approach kidney cell kidney malformation malformation member microdeletion mouse model nephrogenesis novel prenatal response spatiotemporal src Homology Region 2 Domain transcriptome sequencing transcriptomics urinary tract obstruction

项目摘要

PROJECT SUMMARY Up to 50% of worldwide cases of pediatric end-stage kidney failure fall within the spectrum of congenital anomalies of the kidney and urinary tract (CAKUT). Although the genetic bases of CAKUT remain elusive, recent human studies are starting to shed light into the pathogenesis of disease. Studies from our group using a combination of family-based as well as case-control analyses coupled to functional modeling in vertebrates have identified multiple genes that, when mutated in humans, lead to CAKUT. Interestingly, CAKUT phenotypes are described in ~30% of patients with DiGeorge Syndrome, and deletions on chromosome 22q11.2 are the most common cause of DiGeorge syndrome, constituting the most common microdeletion syndrome in humans. To date, our work has shown that haploinsufficiency and point mutations in CRKL, one of the genes found at the 22q11.2 locus, drive kidney and urinary tract malformations in DiGeorge syndrome and sporadic CAKUT; however, the causal mechanisms of human disease occur are still unknown. In both in mice and humans, CRKL exists as at least two main transcripts isoforms, raising the possibility of a complex regulation of CRKL and its binding partner(s) in regulating kidney and urinary tract development. Although some animal studies have shown that manipulation of Crkl in the mouse can lead to kidney phenotypes, none have addressed the role of different Crkl isoforms. This leaves unanswered questions of how each variant is involved and what tissue- and cell-specific roles they play in the modulation of developmental signaling cascades. In an attempt to answer these questions, we devised a multidisciplinary approach that makes use of several mouse models, where one or both transcripts will be genetically ablated in a tissue-specific manner. The experiments proposed herein therefore test the central hypothesis that the two isoforms of Crkl differentially regulate specific events of kidney and urinary tract development, either independently of one another or by modulating the activity of each other. My main goal is to discover how different isoforms of the same gene can have multifaceted effects on the development of the kidney and urinary tract. In Aims 1 and 2, I will address key questions concerning the precise spatiotemporal, and potentially differential, expression pattern of each splice variant, the developmental role of each transcript in the kidney (Aim 1) and urinary tract (Aim 2), and the developmental requirements of one isoform over another. In Aim 3, traditional and transcriptomic/RNAseq approaches will be used to identify key developmental signaling cascades that are affected by the loss of each Crkl isoform in vivo, with findings verified through biochemical and histochemical assays. Ultimately, through the use of developmental genetics and computational approaches to design a novel analytical framework that integrates phenotypic, genetic and single-cell transcriptomic data, I intend to, a) refine searches for novel CAKUT genes, and b) apply findings toward addressing broader, unsolved questions of cell autonomy and secondary responses to genetic insults.

项目总结