Investigation of the role of Mind bomb in epithelial morphogenesis

心灵炸弹在上皮形态发生中作用的研究

• 批准号: 8479467
• 负责人: Miho Matsuda
• 金额: $ 21.38万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8479467
• 关键词: American; Apical; Basic Science; Behavior; Biological Models; Cancer Etiology; Carcinoma; Cell Differentiation process; Cell Polarity; Cell-Cell Adhesion; Cells; Cellular Morphology; Characteristics; Defect; Disseminated Malignant Neoplasm; Embryo; Endocytosis; Epithelial; Epithelial Cells; Goals; Individual; Invaded; Investigation; Lead; Left; Ligands; Malignant - descriptor; Malignant Neoplasms; Mediating; Mesenchymal; Mind; Molecular; Morbidity - disease rate; Morphogenesis; Neoplasm Metastasis; Organ; Organogenesis; Pharmaceutical Preparations; Phenocopy; Play; Process; Property; Proteins; Protocols documentation; Radiation; Research; Role; Sensory; Series; Signal Pathway; Signal Transduction; Site; Therapeutic; Tissues; Zebrafish; abstracting; base; cell fate specification; lateral line; malformation; mortality; mutant; neoplastic cell; notch protein; novel therapeutics; prevent; stem cell division; therapy design; tumor; ubiquitin-protein ligase

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.

项目总结/摘要 转移是指肿瘤细胞失去其固定上皮细胞的一系列过程 特征和获得迁移间充质特征。的转移性癌症 扩散到多个器官是癌症死亡和发病的主要原因。因此，新 迫切需要合理设计的治疗方法来控制、治疗和预防侵袭性疾病， 癌的了解获得高度侵袭性肿瘤的分子机制 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，获得高血糖的关键信号级联之一， 侵入性特征是Notch信号传导。Notch信号传导在细胞凋亡中起着重要的作用， 命运规范、干细胞更新和细胞分化。然而，在决定 侵入性细胞的特征仍然知之甚少。我们的长期目标是阐明 Notch信号及其调节剂决定侵袭细胞的分子机制 特征，从而作为开发新的治疗方案的必要先决条件 用于治疗和预防癌症。我们提出的研究假设是， Notch信号的重要调节剂，思维炸弹（Mib），在 建立和维持上皮细胞形态不仅通过促进Notch 信号传导，而且还通过直接调节上皮细胞极性形成。斑马鱼是一种 优秀的脊椎动物模型系统，以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，以证明 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突变体显示异常的上皮形态发生，2）操作的胚胎 到Notch活性丧失时表现出形态学缺陷，但不能完全复制mib的表型 突变体，和3）Mib相互作用蛋白，Epb4.115，调节上皮极性形成。基于 这些观察，具体的目的是1）定义Notch依赖和独立 Mib在pLL形态发生中的功能，以及2）表征Mib在pLL形态发生中的分子机制。 Notch-independent Mib在上皮形态发生中的功能超过50万美国人 2008年，他们因转移性癌症丧生。在这项拟议的研究中，我们使用斑马鱼， 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理解分子机制， 静止的上皮细胞获得了我们体内的高度侵袭性细胞特征。就会导致 有效预防和治疗侵袭性癌症的新疗法。