Delineating a role for non-canonical wnt signaling in PKD

描述(申请人提供)：尽管它们是生物学中一些最常见的结构，但调控上皮管形成的确切分子和细胞过程仍然未知。最近的几项研究表明，平面细胞极性(PCP)在包括多囊肾病在内的各种肾小管疾病的发生和/或发展中起作用。然而，目前尚不清楚平面细胞分化是如何建立的，也不清楚它对小管发育有什么影响。在过去的几年里，我们已经创造并鉴定了一些遗传和化学方法来干扰和分析小鼠肾脏中的五氯苯酚。我们发现，Wnt信号是肾小管上皮细胞平面定位所必需的，而这一过程中的缺陷与囊肿的形成有关。然而，我们不知道为什么。我们假设Wnt信号介导间质的图案化，并且间质信号建立PCP。此外，我们假设细胞的定向运动是建立和维持适当的肾小管直径所必需的。在这项提案中，我们将使用基因工程和活细胞成像的组合来测试这些假说，并确定这些过程是否在PKD的同源模型中受到干扰。

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.