Circadian clock regulation of branching morphogenesis during kidney development

肾脏发育过程中分支形态发生的昼夜节律时钟调节

基本信息

批准号：
9405862
负责人：
ROSEMARY V SAMPOGNA
金额：
$ 36万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9405862
关键词：
ARNTL gene Adult Affect Aging Alzheimer&apos s Disease Animal Model Animals Autistic Disorder Automobile Driving Biochemical Biological Clocks Biological Process Biology Birth Cardiovascular Diseases Childhood Chronic Kidney Failure Circadian Rhythms Clock protein Complex Congenital Abnormality Data Data Set Databases Defect Development Developmental Process Diabetes Mellitus Diagnosis Dimensions Disease Embryo Etiology Event Experimental Animal Model Filtration Future Gene Expression Genes Genetic Genomics Growth Hour Human Hypertension Image Injury Kidney Kidney Diseases Kidney Failure Lead Life Link Low Birth Weight Infant Maps Measures Mesenchyme Metabolic syndrome Metanephric Diverticulum Methods Molecular Morphogenesis Mutation Nephrons Obesity Organism Organogenesis Pathway interactions Patients Pattern Periodicity Phase Phenotype Physiological Physiology Population Process Regulation Renal Mass Reporter Resolution Risk Series Signal Transduction Sleep Disorders Stress Structural defect Structure Techniques Testing Therapeutic Intervention Time Tissues Transcript Trees Urinary tract Work bioluminescence imaging body system circadian pacemaker exome in vivo interest malformation mutant neglect nephrogenesis novel overexpression premature process repeatability programs promoter protein expression public health relevance three dimensional structure trait transcription factor transcriptome transcriptomics transmission process

项目摘要

DESCRIPTION (provided by applicant): Developmental defects of the urinary tract are the most common cause of pediatric kidney failure. In humans, kidney development does not progress after birth therefore the number of nephrons (filtration units) is permanently decreased in the setting of prematurity, low birth weight, intrauterine stress and congenital kidney defects. This reduction in renal reserve has in turn been linked to increased risk of hypertension and chronic kidney disease of diverse etiology in the adult population. Thus much of the burden of pediatric and adult renal disease originates from developmental defects, indicating that elucidation of molecular mechanisms of organogenesis may provide significant opportunities for diagnosis, intervention and therapy. Mammalian kidneys develop via a process of repeating bi-directional signaling between the ureteric bud (UB) and metanephric mesenchyme (MM) that ultimately generates and organizes ~1 million nephrons per kidney. Although it is well established that reciprocal transmission of UB- and MM-derived signals drive specific aspects of nephron formation, central genetic regulation of this developmental process remains undefined. We have developed a longitudinal method that reconstructs the three-dimensional kidney with respect to time and analyzes detailed morphometric parameters throughout development. When devising this approach, we in parallel discovered that cyclical circadian clock gene expression correlated with timing of branching events and with nephron number. Moreover, mutation of core clock genes resulted in significant kidney structural defects. We hypothesize that the circadian clock coordinates the repetitive mechanisms of kidney development by regulating precise exchange of molecular signals between the UB and MM. This proposal aims to use real time bioluminescent imaging of rhythmic signals, high-resolution phenotype analysis as well as genetic and biochemical methods to comprehensively characterize the circadian regulation of branching and nephron formation during kidney development. We outline a unique opportunity to discover novel molecules required for kidney development by exploiting circadian biology.

描述（由适用提供）：尿路的发育缺陷是小儿肾衰竭的最常见原因。在人类中，肾脏发育不会在出生后进展，因此在早产，低出生体重，宫内胁迫和先天性肾脏缺陷的情况下，肾单位的数量（过滤单元）永久减少。肾脏储备的减少反过来又与成年人口中潜水员病因的高血压和慢性肾脏疾病的风险增加有关。小儿和成人肾脏疾病的大部分燃烧源于发育缺陷，表明阐明器官发生的分子机制可能为诊断，干预和治疗提供了重要的机会。哺乳动物的肾脏通过在输尿管芽（UB）和元语间充质（MM）之间重复双向信号传导的过程开发，该过程最终会产生并组织每个肾脏约100万个肾脏。尽管可以很好地确定，UB和MM衍生信号的相互传播推动了肾单位形成的特定方面，但这种发育过程的中心遗传调节仍然不确定。我们已经开发了一种纵向方法，该方法可以在时间上重建三维肾脏，并在整个发育过程中分析详细的形态学参数。设计这种方法时，我们并行发现周期性昼夜节律基因表达与分支事件的时间和肾单位数相关。此外，核心时钟基因的突变导致了明显的肾脏结构缺陷。我们假设昼夜节律时钟通过调节UB和MM之间的分子信号的精确交换来协调肾脏发育的重复机制。该建议旨在利用节奏信号的实时生物发光成像，高分辨率表型分析以及遗传和生化方法，以全面地表征肾脏发育过程中分支和肾脏形成的昼夜节律调节。我们概述了一个独特的机会，可以通过利用昼夜节律生物学来发现肾脏发育所需的新分子。