Ureteric Bud Patterning

输尿管芽图案

• 批准号: 7755899
• 负责人: DORIS A HERZLINGER
• 金额: $ 32.12万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 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/7755899
• 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

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（由申请方提供）：哺乳动物肾脏发育依赖于输尿管芽。其近端诱导发育中的肾脏中的肾单位形成，并经历形成肾内收集系统的分支形态发生，而其远端或主干域分化成输尿管。输尿管芽形态发生的异常调节可导致一系列先天性缺陷，最常见的是输尿管重复和梗阻。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传导途径仍然知之甚少，这些都是尿液不受阻碍地流向膀胱所必需的。该建议的重点是输尿管形态发生。在目标1中，将在Bmp 4基因剂量严重敲低的小鼠中分析Bmp信号传导在限制输尿管芽生长到沿着泌尿道沿着的单个位点和控制输尿管平滑肌分化中的作用，所述Bmp 4基因剂量支持胚胎存活至出生，但不超过出生。将使用Cre-lox技术和现有的小鼠品系完成诱导型Bmp 4敲低。将在发育的不同阶段敲除bmp 4，从其在控制终末输尿管分化中的作用出发，分别分析该信号因子在调节输尿管数量中的作用。在目标2中，我们将分析一个缺乏Pbx 1（一种hox基因辅因子）表达的小鼠品系。我们已经发现，Pbx 1是必不可少的限制Bmp 4信号和平滑肌形成输尿管。这种突变株系将用于解剖控制肾脏和输尿管之间边界平滑肌组织的遗传途径和细胞类型，肾脏和输尿管是新生儿尿路梗阻最常见的部位。这些实验的成功完成将提供深入了解先天性缺陷的输尿管形态发生的易感性。公共卫生相关性：输尿管是一种将废物从肾脏运送到膀胱的肌肉管，在人类中极易发生先天性缺陷。然而，在发育胚胎中指导输尿管形成的机制仍然知之甚少。在这个建议中，我们将测试几个假设解释的易感性，这一段泌尿道缺陷。