Delineating a role for non-canonical wnt signaling in PKD

描述（由申请人提供）：尽管它们是生物学中一些最常见的结构，但调控上皮小管形成的精确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）有助于各种肾小管疾病（包括多囊肾病）的发生和/或进展。然而，平面细胞极化是如何建立的，以及它对小管发育有什么影响，目前还不清楚。在过去的几年里，我们已经产生和表征了一些遗传和化学方法，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平面定向所必需的，并且该过程中的缺陷与囊肿形成相关。然而，我们不知道为什么。我们假设Wnt信号介导基质的模式化，基质信号建立PCP。此外，我们假设，定向细胞运动需要建立和维持适当的肾小管直径。在这项提议中，我们将使用基因工程和活细胞成像的组合来测试这些假设，并确定这些过程是否在PKD的orthopathy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.