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

• 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
• 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' 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

 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（由申请方提供）：尿路发育缺陷是小儿肾衰竭的最常见原因。在人类中，肾脏发育在出生后不会进展，因此在早产、低出生体重、宫内应激和先天性肾缺陷的情况下，肾单位（滤过单位）的数量永久性减少。 这种肾储备的减少反过来又与成年人群中不同病因的高血压和慢性肾脏疾病的风险增加有关。因此，许多儿童和成人肾脏疾病的负担源于发育缺陷，表明阐明器官发生的分子机制可能为诊断，干预和治疗提供重要的机会。哺乳动物肾脏通过输尿管芽（UB）和后肾间充质（MM）之间重复双向信号传导的过程发育，最终每个肾脏产生和组织约100万个肾单位。虽然它是公认的相互传输UB和MM衍生的信号驱动特定方面的肾单位形成，中央遗传调控这一发展过程仍然不明确。我们已经开发了一种纵向的方法，重建三维肾脏相对于时间和分析详细的形态学参数在整个发展。在设计这种方法时，我们同时发现周期性生物钟基因表达与分支事件的时间和肾单位数量相关。此外，核心时钟基因的突变导致显著的肾脏结构缺陷。我们假设，昼夜节律钟协调肾脏发育的重复机制，通过调节UB和MM之间的分子信号的精确交换。这项建议的目的是使用真实的时间生物发光成像的节奏信号，高分辨率的表型分析以及遗传和生化方法，全面表征的昼夜节律调节的分支和肾单位形成在肾脏发育过程中。我们概述了一个独特的机会，发现肾脏发育所需的新分子，利用昼夜节律生物学。