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征，获得迁移间质特征的一系列过程。转移性癌症扩散到多个器官是癌症死亡率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、治愈和预防侵袭性癌症。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，获得高侵入性特征的关键信号级联之一是Notch信号。Notch信号在细胞命运规范、干细胞更新和细胞分化中起着很好的作用。然而，在确定侵袭性细胞特征中的作用仍然知之甚少。候选人的长期目标是阐明Notch信号及其调节剂决定侵袭性细胞特征的分子机制，从而为开发治疗和预防癌症的新治疗方案提供必要的前提。本研究的假设是Notch信号的重要调节剂Mind bomb （Mib）不仅通过促进Notch信号传导，而且通过直接调节上皮细胞极性形成，在建立和维持上皮细胞形态中起关键作用。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）作为模型系统来证明Mib在上皮形态发生中的双重作用。这位候选人基于以下观察得出她的假设：1)mib突变体表现出异常的上皮形态发生，2)被操纵使Notch活性丧失的胚胎表现出形态缺陷，但不会完全表型上的mib突变，以及3)mib相互作用蛋白Epb4.115调节上皮极性的形成。基于这些观察结果，Specific Aim 1将定义Mib在pLL形态发生中的notch依赖和独立功能，而Specific Aim 2将描述Mib在上皮形态发生中notch独立功能的分子机制。

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.