Signaling Mechanisms Controlling Planar Cell Polarity

在发育过程中，许多组织中的上皮细胞获得与它们的极性正交的极性。 顶基轴这种极性，称为平面细胞极性（PCP），或组织 极性是正常生理功能所必需的。早期对五氯苯酚的研究主要集中在 昆虫上皮细胞，事实上，我们对PCP的大部分机械理解来自于 果蝇作为模型系统的持续使用。然而，一系列 医学上重要的发育缺陷和生理过程是在 控制五氯苯酚的机制，这些机制似乎可以保护大部分或全部机制， 在果蝇中发现的五氯苯酚，引起了人们对研究果蝇和 在脊椎动物模型系统中。 PCP的缺陷会导致一系列发育异常和疾病。也许 其中最具特征的是，PCP是正确定位感觉器官所必需的。 内耳柯替氏器中的毛细胞，缺陷会导致耳聋。其他 人类和模式生物中与五氯苯酚有关的发育缺陷包括开放性 神经管缺陷、多囊肾和心脏圆锥干缺陷。五氯苯酚还被 被认为是特发性肺动脉高压发病机制的基础， 在恶性细胞的侵袭和转移过程中发生的定向迁移。 尽管近年来取得了相当大的进展， 信号模块，它们之间的相互作用还不够 因此，限制了潜在的治疗机会。 对这些疾病的干预。 这项提案的目标是将复杂的遗传学、显微镜和 生物化学/蛋白质组学的方法来研究五氯苯酚在果蝇。通过这样做，我们 希望能增进我们对这一重要机制的理解，并促进 为这些PCP为基础的疾病的诊断和治疗工具的发展。

During development, epithelial cells in many tissues acquire a polarity orthogonal to their apical-basal axis. This polarity, referred to as planar cell polarity (PCP), or tissue polarity, is essential for normal physiological function. Early studies of PCP focused on insect epithelia, and indeed, most of our mechanistic understanding of PCP derives from the ongoing use of the fruitfly, Drosophila, as a model system. However, a range of medically important developmental defects and physiological processes are under control of PCP mechanisms that appear to conserve much or all of the mechanism uncovered in flies, driving considerable interest in studying PCP both in Drosophila and in vertebrate model systems. Defects in PCP result in a range of developmental anomalies and diseases. Perhaps best characterized among these, PCP is required for the correct orientation of sensory hair cells in the organ of Corti of the inner ear, and defects result in deafness. Other PCP related developmental defects in humans and in model organisms include open neural tube defects, polycystic kidneys, and conotruncal heart defects. PCP is also believed to underlie the pathogenesis of idiopathic pulmonary hypertension and the directed migration that occurs during invasion and metastasis of malignant cells. Despite considerable progress in recent years, the molecular mechanisms of the PCP signaling modules, and the interactions between them are as yet insufficiently understood, thereby limiting the potentially substantial opportunities for therapeutic interventions for these disorders. The goal of this proposal is to apply sophisticated genetics, microscopy and biochemical/proteomic methods to the study of PCP in the fruitfly. By doing so, we expect to advance our understanding of this important mechanism, and facilitate the development of diagnostic and therapeutic tools for these PCP-based disorders.