Delineating a role for non-canonical wnt signaling in PKD

描述非规范 wnt 信号在 PKD 中的作用

• 批准号: 8652448
• 负责人: Thomas Joseph Carroll
• 金额: $ 34.58万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-15 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8652448
• 关键词: Ablation; Address; Adult; Affect; Binding; Biology; Cadherins; Caliber; Cell Polarity; Cell physiology; Cells; Clinical Research; Cyst; Defect; Development; Dimensions; Disease; Distal; Duct (organ) structure; Ectopic Expression; Epithelial; Epithelium; Event; Fibroblasts; Gene Expression; Gene Targeting; Genetic; Genetic Engineering; Grant; Individual; Kidney; Length; Life; Maintenance; Mediating; Methods; Microscopic; Modeling; Modification; Molecular; Morphogenesis; Movement; Mus; Mutation; Nephrons; Organ Culture Techniques; Organ Transplantation; Organism; Orthologous Gene; Pattern; Phenotype; Play; Polycystic Kidney Diseases; Process; Production; Reagent; Renal tubule structure; Research Personnel; Role; Shapes; Signal Transduction; Structure; System; Techniques; Testing; Therapeutic; Therapeutic Studies; Transcript; Transgenic Mice; Tubular formation; Width; Work; cell motility; cell type; cellular imaging; chemical genetics; cost effective; direct application; fly; human disease; insight; interest; mutant; overexpression; public health relevance; reproductive; respiratory; small molecule

DESCRIPTION (provided by applicant): Despite the fact that they are some of the most common structures in biology, the precise molecular and cellular processes that regulate the formation of epithelial tubules are still unknown. Several recent studies have suggested planar cell polarity (PCP) contributes to the development and/or progression of various tubular diseases including polycystic kidney disease. However, it is still not clear how planar cell polariy is established or what effects it has on tubule development. Over the last several years, we have generated and characterized a number of genetic and chemical methods for perturbing and analyzing PCP in the mouse kidney. We have discovered that Wnt signaling is required for planar orientation of cells within the kidney tubular epithelium and that defects in this process are associated with cyst formation. However, we don't know why. We hypothesize that Wnt signaling mediates patterning of the stroma and that stromal signals establish PCP. Further, we hypothesize that oriented cell movement is required to establish and maintain the proper diameter of kidney tubules. In this proposal, we will use a combination of genetic engineering as well as live cell imaging to test these hypotheses as well as determining whether these processes are perturbed in orthologous models of PKD.

描述（由申请人提供）：尽管它们是生物学中最常见的结构，但调节上皮小管形成的精确分子和细胞过程仍然未知。最近的一些研究表明，平面细胞极性（PCP）有助于各种管状疾病（包括多囊肾脏疾病）的发展和/或进展。但是，尚不清楚平面细胞极化是如何建立的或它对小管发育的影响。在过去的几年中，我们生成并表征了许多遗传和化学方法，用于扰动和分析小鼠肾脏中的PCP。我们已经发现，Wnt信号传导是肾小管上皮细胞的平面取向所必需的，并且此过程中的缺陷与囊肿形成有关。但是，我们不知道为什么。我们假设Wnt信号传导介导基质的模式，而基质信号建立了PCP。此外，我们假设需要定向细胞运动来建立和维持肾小管的正确直径。在此提案中，我们将结合基因工程和活细胞成像来检验这些假设，并确定这些过程是否在PKD的直系同源模型中扰动。