Investigation of the role of Mind bomb in epithelial morphogenesis

项目摘要/摘要 转移是指肿瘤细胞失去静止的上皮细胞的一系列过程 并获得迁移性间充质特征。转移性癌症 扩散到多个器官是癌症死亡和发病率的主要原因。因此，新的 迫切需要合理设计的治疗方法来控制、治愈和预防入侵 癌症。了解获得高度侵袭性骨肉瘤的分子机制 这些特征将有助于开发预防和治疗癌症的新疗法。 越来越多的证据表明，收购Highly的关键信号级联之一 侵袭性特征是Notch信号。Notch信号在细胞中发挥着独特的作用 命运规范、干细胞更新和细胞分化。然而，在决定 侵袭性细胞的特征仍然知之甚少。我们的长期目标是澄清 Notch信号及其调节器决定侵袭细胞的分子机制 特点，从而成为开发新的治疗方案的必要前提 用于治疗和预防癌症。我们提议的研究的假设是一个 Notch信号的基本调节器，心灵炸弹(MIB)，在 建立和维持上皮细胞形态不仅仅是通过促进Notch 不仅通过信号转导，还通过直接调节上皮细胞的极性形成。斑马鱼是一种 优秀的脊椎动物模型系统，可可视化单个细胞的行为。在这项研究中，我们使用 斑马鱼的感觉器官，后侧线(PLL)，作为一个模型系统来演示 Mib在上皮形态发生中的双重作用。我们的假设基于以下几点 观察到1)mib突变体表现出异常的上皮形态发生，2)胚胎被操纵 Notch活性的丧失表现为形态缺陷，但不能完全复制MIB 突变，以及3)MIB相互作用蛋白Epb4.115，调节上皮极性的形成。基于 这些观察的具体目的是：1)定义凹槽依赖和独立 Mib在PLL形态发生中的作用，以及2)表征PLL形态发生的分子机制 MIB在上皮形态发生中的非缺口依赖功能。超过50万美国人 他们在2008年死于转移性癌症。在这项拟议的研究中，我们使用斑马鱼来 了解上皮形态发生的分子机制。圆满完成 我们提出的研究将适用于了解分子机制，通过 静止的上皮细胞在我们的体内获得了高度侵袭的细胞特征。它将导致 有效预防和治疗浸润性癌症的新疗法。

Project Summary/Abstract Metastasis is a series of process that tumor cells lose their stationary epithelial characteristics and acquire migratory mesenchymal characteristics. Metastatic cancer that spread to multiple organs is a major cause of cancer mortality and morbidity. Thus, new rationally designed therapies are urgently needed to control, cure and prevent invasive cancers. Understanding the molecular mechanisms for the acquisition of highly invasive characteristics will contribute to developing new therapies for preventing and treating cancers. Growing evidence suggests that one of the critical signaling cascades for the acquisition of highly invasive characteristics is Notch signaling. Notch signaling plays a well-characterized role in cell fate specifications, stem cell renewals, and cell differentiation. However, the role in determining invasive cell characteristics remains poorly understood. Our long-term goal is to elucidate the molecular mechanisms by which Notch signaling and its modulators determines the invasive cell characteristics, thus serving as a necessary prerequisite to developing new therapeutic protocols for treating and preventing cancers. The hypothesis of our proposed research is that an essential modulator of Notch signaling, Mind bomb (Mib), plays a critical role in establishing and maintaining epithelial cell morphology not only by promoting Notch signaling but also by directly regulating epithelial cell polarity formation. The zebrafish is an excellent vertebrate model system to visualize the behavior of individual cells. In this study we use the zebrafish sensory organ, the posterior lateral line (pLL), as a model system to demonstrate these dual roles of Mib in epithelial morphogenesis. We based our hypothesis on the following observations that 1)mib mutants show aberrant epithelial morphogenesis, 2)embryos manipulated to loss of Notch activity show morphological defects, but do not completely phenocopy mib mutants, and 3)a Mib interacting protein, Epb4.1l5, regulates epithelial polarity formation. Based on these observations, the specific aims are to 1)define the Notch-dependent and independent function of Mib in pLL morphogenesis, and 2)characterize the molecular mechanism of Notch-independent Mib function in epithelial morphogenesis. More than 500,000 Americans lost their lives to metastatic cancer in 2008. In this proposed study, we use the zebrafish to understand the molecular mechanism of epithelial morphogenesis. The successful completion of our proposed research will be applicable to understanding molecular mechanisms by which stationary epithelial cells acquire the highly invasive cell characteristic in our bodies. It will lead to new therapies that effectively prevent and treat invasive cancers.