The Role of Bicaudal-C in Polycystic Kidney Disease

描述（由申请人提供）：多囊肾疾病（PKD）是终末期肾衰竭的主要原因，其特征是沿着整个肾单位长度形成肾囊肿。他们需要广泛的治疗，如透析和肾移植。由于对肾囊肿形成的分子机制仍知之甚少，因此PKD的治疗形式有限。多年来，在鉴定人类PKD形式中突变的基因以及开发动物模型以研究这些有害疾病的发病机制方面取得了相当大的进展。除了小鼠和大鼠PKD模型之外，爪蟾或斑马鱼的更原始的前肾已经成为研究引起PKD的上皮畸形的分子机制的替代模型系统。由于其快速发展和易于分子操作，前肾是研究人或小鼠PKD的理想伴侣系统。在本研究中，我们将利用小鼠后肾和两栖类前肾来研究RNA结合分子Bicaudal-C。缺乏Bicaudal-C蛋白的小鼠早在胚胎第15.5天就出现肾囊肿。首先在肾小球中检测到囊肿形成，但随后可沿肾单位的整个长度沿着检测到。类似地，在非洲爪蟾中，双尾-C的缺失在原肾中诱导“PKD样”表型。重要的是，肾脏发育中Bicaudal-C活性的分子机制及其与人PKD中突变的基因（即多囊蛋白-1、多囊蛋白-2和多导管蛋白/纤维囊蛋白）的联系仍不清楚。本提案将解决这些问题。我们将测试的假设，Bicaudal-C是一个涉及多囊肾疾病的基因的翻译调节。它基于四个观察结果：（1）Bicaudal-C突变小鼠在囊肿形成开始前具有降低的多囊蛋白-2 mRNA和蛋白水平。(2)Polycystin-2的调节是转录后的。(3)Bicaudal-C蛋白定位于P小体，在果蝇和C. elegans在转录后水平调节一组选定的mRNA。(4)许多PKD基因在其3' UTR中具有进化上保守的miRNA结合位点。如果成功，这项研究将提供新的见解，潜在的生物和生化途径，导致肾囊肿形成的PKD。它将把一个最不了解的PKD基因整合到现有的PKD模式中。因此，它将直接适用于未来的研究PKD，并可能提供一个新的角度治疗干预。

DESCRIPTION (provided by applicant): Polycystic Kidney Diseases (PKD) are the leading cause of end-stage renal failure and are characterized by the development of renal cysts along the entire length of the nephron. They require extensive treatments, such as dialysis and kidney transplantation. Only limited forms of therapy for PKD exist, since the molecular mechanisms underlying the formation of renal cysts are still poorly understood. Over the years, considerable progress has been made in identifying genes mutated in human forms of PKD and in the development of animal models to study the pathogenesis of these detrimental diseases. Besides mouse and rat PKD models, the more primitive pronephric kidney of Xenopus or zebrafish has emerged as an alternative model system to study the molecular mechanisms underlying the epithelial malformations causing PKD. With its fast development and ease of molecular manipulations, the pronephric kidney is an ideal companion system to the study of PKD in humans or mice. In this proposal we will use the mouse metanephros and the amphibian pronephros to study the RNA binding molecule Bicaudal-C. Mice lacking Bicaudal-C protein develop renal cysts as early as embryonic day 15.5. Cyst formation is first detected in the glomerulus, but can later be detected along the entire length of the nephron. Similarly, in Xenopus, loss-of-Bicaudal-C induces a "PKD-like" phenotype in the pronephros. Importantly, the molecular mechanism of Bicaudal-C activity in kidney development and its connection to the genes mutated in human PKD, i.e. Polycystin-1, Polycystin-2 and Polyductin/Fibrocystin is still not understood. This proposal will address these questions. We will test the hypothesis that Bicaudal-C is a translational regulator of genes involved in Polycystic Kidney Disease. It is based on four observations: (1) Bicaudal-C mutant mice have reduced Polycystin-2 mRNA and protein levels before the onset of cyst formation. (2) The regulation of Polycystin-2 is posttranscriptional. (3) Bicaudal-C protein is localized to P-Bodies and has been shown in Drosophila and C. elegans to regulate a selected group of mRNAs at the posttranscriptional level. (4) Many PKD genes have evolutionary conserved miRNA binding sites in their 3' UTR. If successful, this study will provide novel insights to the underlying biological and biochemical pathways leading to the renal cyst formation in PKD. It will integrate one of the least understood PKD genes into the existing paradigms of PKD. As such, it will be directly applicable to future studies of PKD and may provide a new angle for therapeutic interventions.