Ureteric Bud Patterning

输尿管芽图案

基本信息

批准号：
7566771
负责人：
DORIS A HERZLINGER
金额：
$ 32.35万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-15 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7566771
关键词：
Alleles Birth Bladder Cell Lineage Cephalic Characteristics Congenital Abnormality Cues Data Defect Development Distal Duct (organ) structure Embryo Embryonic Development Encapsulated Epithelial Etiology Event Excision Exhibits Fibroblasts Fibrous capsule of kidney Gene Dosage Genes Genetic Genetic Recombination Genotype Germ Lines Human In Vitro Kidney Knockout Mice Mediating Messenger RNA Metanephric Diverticulum Morphogenesis Mus Muscle Muscle function Mutant Strains Mice Nephrons Newborn Infant Obstruction Pathway interactions Pattern Pelvis Phenotype Positioning Attribute Predisposition Prevention Process Publishing Regulation Role Signal Pathway Signal Transduction Site Smooth Muscle Staging System Technology Testing Tissues Transcriptional Regulation Tube Ureter Urinary tract Urine Waste Products Work cell type cofactor in vivo insight knock-down mutant nephrogenesis prevent progenitor public health relevance research study urinary tract obstruction

项目摘要

DESCRIPTION (provided by applicant): Mammalian renal development is dependent on the ureteric bud. Its proximal tip induces nephron formation in the developing kidney and undergoes branching morphogenesis forming the intra-renal collecting system whereas its distal or trunk domain differentiates into the ureter. Abnormal regulation of ureteric bud morphogenesis can result in a spectrum of congenital defects, the most common being ureteral duplications and obstructions. Yet the tissue interactions and signaling pathways that limit ureter number and control ureteral smooth muscle differentiation required for the un-obstructed flow of urine to the bladder remain poorly understood. This proposal is focused on ureter morphogenesis. In Aim 1, the role of Bmp signaling in restricting ureteric bud outgrowth to a single site along the urinary tract and in controlling ureteral smooth muscle differentiation will be analyzed in mice with a severe knockdown in Bmp4 gene dosage that supports embryonic viability to birth, but not beyond. Inducible Bmp4 knockdown will be accomplished using Cre-lox technology and existing mouse lines. Bmp4 will be knocked down at different stages of development to analyze the role of this signaling factor in regulating ureter number separately, from its role in controlling terminal ureter differentiation. In Aim 2, we will analyze a mouse line lacking expression of Pbx1, a hox gene cofactor. We have discovered that Pbx1 is essential for restricting Bmp4 signaling and smooth muscle formation to the ureter. This mutant line will be used to dissect the genetic pathways and cell type (s) that control the organization of smooth muscle at the border between the kidney and the ureter, the most common site of urinary tract obstructions in newborns. The successful completion of these experiments will provide insight into the susceptibility of ureter morphogenesis to congenital defects. PUBLIC HEALTH RELEVANCE: The ureter, a muscular tube that transports waste products from the kidneys to the bladder, is highly prone to congenital defects in humans. However, the mechanisms guiding ureter formation in the developing embryo remain poorly understood. In this proposal, we will test several hypotheses explaining the susceptibility of this urinary tract segment to defects.

描述（由申请人提供）：哺乳动物的肾脏发育取决于输尿管芽。它的近端尖端在发育中的肾脏中诱导肾单位形成，并进行分支形态发生，形成形成肾脏内收集系统，而其远端或躯干结构域则与输尿管区分开。输尿管芽形态发生异常调节会导致一系列先天性缺陷，最常见的是输尿管重复和障碍物。然而，限制输尿管数量和控制输尿管平滑肌分化的组织相互作用和信号通路，尿液流向膀胱所需的流动所需的肌肉分化仍然很众所周知。该建议的重点是输尿管形态发生。在AIM 1中，BMP信号传导在将输尿管芽的产物限制为沿尿路的单个部位以及控制输尿管平滑肌分化方面的作用将在小鼠中分析，而BMP4基因剂量严重敲低，以支持胚胎的疾病，但支持出生的胚胎活力，但是不超越。可诱导的BMP4敲低将使用CRE-LOX技术和现有鼠标线完成。 BMP4将在开发的不同阶段被击倒，以分别分析该信号因子在控制终端输尿管分化中的作用，分别调节输尿管数。在AIM 2中，我们将分析缺乏HOX基因辅因子PBX1表达的小鼠线。我们发现PBX1对于将BMP4信号传导和平滑肌形成限制为输尿管至关重要。该突变线将用于剖析控制肾脏和输尿管之间边界的平滑肌组织的遗传途径和细胞类型，这是新生儿尿路阻塞的最常见部位。这些实验的成功完成将洞悉输尿管形态发生对先天性缺陷的敏感性。公共卫生相关性：输尿管是一种将废物从肾脏传输到膀胱的肌肉管，非常容易发生人类先天性缺陷。但是，指导输尿管在发育中的胚胎中形成的机制仍然吸引人了解。在此提案中，我们将检验一些假设，以解释该尿路细分市场缺陷的敏感性。