Investigation of the role of Mind bomb in epithelial morphogenesis

描述(申请人提供)：转移是肿瘤细胞失去其静止的上皮特性而获得迁移性间充质特性的一系列过程。扩散到多个器官的转移性癌症是癌症死亡和发病率的主要原因。因此，迫切需要新的合理设计的治疗方法来控制、治愈和预防浸润性癌症。了解获得这种高侵袭性特征的分子机制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，Notch信号是获得高度侵袭性特征的关键信号级联之一。Notch信号在细胞命运、干细胞更新和细胞分化中扮演着重要的角色。然而，决定侵袭性细胞特性的作用仍然知之甚少。候选人的长期目标是阐明Notch信号及其调节器决定侵袭细胞特性的分子机制，从而为开发治疗和预防癌症的新治疗方案提供必要的先决条件。这项研究的假设是，作为Notch信号的重要调节器，心灵炸弹(Mind Bomb，MIB)不仅通过促进Notch信号，而且通过直接调节上皮细胞的极性形成，在建立和维持上皮细胞形态方面发挥关键作用。斑马鱼是一个很好的脊椎动物模型系统，可以可视化单个细胞的行为。在这项研究中，她使用斑马鱼的感觉器官后侧线(PLL)作为模型系统来演示Mib在上皮形态发生中的双重作用。这位候选人的假设基于以下观察结果：1)MIB突变体显示异常的上皮形态发生，2)Notch活性丧失的胚胎显示出形态缺陷，但不完全复制MIB突变体，以及3)MIB相互作用蛋白Epb4.115调节上皮极性的形成。在这些观察的基础上，特异性目标1将确定Mib在PLL形态发生中的Notch依赖和独立功能，而特异性目标2将描述Notch非依赖性Mib功能在上皮形态发生中的分子机制。 2008年，超过50万美国人死于转移性癌症。在这项拟议的研究中，候选人使用斑马鱼来了解上皮形态发生的分子机制。这项研究的成功完成将有助于理解静止上皮细胞在人体内获得高度侵袭性细胞特性的分子机制。它将导致有效预防和治疗浸润性癌症的新疗法。 研究背景：转移是指肿瘤细胞失去其静止的上皮特征而获得迁移性间质特征的一系列过程。2008年，超过50万美国人死于转移性癌症。了解获得高侵袭性特征的分子机制将有助于开发预防和治疗癌症的治疗方案。

DESCRIPTION (Provided by Applicant): 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 such 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. The candidate's 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 the 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 she uses the zebrafish sensory organ, the posterior lateral line (pLL), as a model system to demonstrate these dual roles of Mib in epithelial morphogenesis. The candidate based her 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, Epb4.115, regulates epithelial polarity formation. Based on these observations, Specific Aim 1 will define the Notch-dependent and independent function of Mib in pLL morphogenesis, and Specific Aim 2 will 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, the candidate uses the zebrafish to understand the molecular mechanism of epithelial morphogenesis. The successful completion of the 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. RELEVANCE: Metastasis is a series of process that tumor cells lose their stationary epithelial characteristics and acquire migratory mesenchymal characteristics. More than 500,000 Americans lost their lives to metastatic cancer in 2008. Understanding the molecular mechanisms for the acquisition of highly invasive characteristics will contribute to developing therapeutic protocols for preventing and treating cancers.