Role of Fibroblast-Growth Factor Signalling in Epithelial Remodelling

成纤维细胞生长因子信号传导在上皮重塑中的作用

• 批准号: G0901020/1
• 负责人: Arno Muller
• 金额: $ 41.51万
• 依托单位: University of Dundee
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0901020%2F1
• 关键词: Role; Fibroblast; Growth; Factor; Signalling

Our body is composed of different organs and tissues, which all work together to deliver the functions that identify us as healthy human beings. The major types of tissues in our body are sheet-like assemblies of cells, called epithelia. Epithelia have a top and a bottom side. The top or apical side faces the outside world (skin) or the lumen of an organ (gut, glands, kidney) and the bottom or basal side faces the inside of the organism. This polarized architecture is essential for the function of epithelia. For example a disruption of the gut epithelium will impair uptake of nutrients and eventually cause inflammation. Loss of epithelial polarity can also cause diseases such as fibrosis, where excessive connective tissue is formed. Moreover, loss of epithelial polarity is a key event in the dissemination of cancer cells into different parts of the body, a process called metastasis. The mechanisms that cancer cells utilize to become malignant are often recapitulations of events that normally occur during embryogenesis. During development a primitive embryonic epithelium is formed that partially undergoes a conversion to non-epithelial (mesenchymal) cells. These mesenchymal cells develop further into muscles, heart and blood cells. Improper cell movements during these stages of development can result in abortive development and congenital defects in animals and humans.Our research project addresses the question how cell signalling can elicit the transition of an epithelial cell to a mesenchymal cell (called EMT). Our laboratory will utilize genetics to identify molecules important for epithelial cells to loose their epithelial polarity in EMT. Research on human embryos is highly problematic for obvious ethical reasons. Modern biomedical research uses model organisms to study basic biological mechanisms because these are often very similar in different organisms. For example the principle genes that control cell division are quite similar from yeast to man. We utilize the fruit fly as a model system to find genes that are involved in EMT. The principal molecules that control the development of the fly are also critical for the development of human embryos. This finding was awarded the Nobel Prize for Medicine in 1995. Furthermore, more than 75% of all genes that have been identified to cause diseases in humans are also present in the fly. Therefore the fly is an excellent system to perform detailed research which findings can eventually be translated from the basic research laboratory to the clinic.

我们的身体由不同的器官和组织组成，它们共同发挥功能，使我们成为健康的人类。我们身体中的主要组织类型是片状的细胞集合体，称为上皮细胞。上皮有顶面和底面。顶部或顶侧面向外部世界（皮肤）或器官（肠道、腺体、肾脏）的内腔，底部或基侧面向生物体的内部。这种极化结构对于上皮细胞的功能是必不可少的。例如，肠上皮细胞的破坏将损害营养物质的吸收并最终导致炎症。上皮极性的丧失也可引起疾病，如纤维化，其中形成过多的结缔组织。此外，上皮极性的丧失是癌细胞扩散到身体不同部位的关键事件，这一过程称为转移。癌细胞用于变成恶性的机制通常是胚胎发生期间正常发生的事件的重演。在发育过程中，形成原始胚胎上皮，其部分地经历向非上皮（间充质）细胞的转化。这些间充质细胞进一步发育成肌肉、心脏和血细胞。在这些发育阶段，细胞运动不当可能导致动物和人类发育失败和先天性缺陷。我们的研究项目解决了细胞信号传导如何引起上皮细胞向间充质细胞转变（称为EMT）的问题。我们的实验室将利用遗传学来确定上皮细胞在EMT中失去上皮极性的重要分子。由于明显的伦理原因，对人类胚胎的研究存在很大问题。现代生物医学研究使用模式生物来研究基本的生物学机制，因为这些机制在不同的生物体中通常非常相似。例如，控制细胞分裂的主要基因从酵母到人类都非常相似，我们利用果蝇作为模型系统来寻找参与EMT的基因。控制果蝇发育的主要分子对人类胚胎的发育也至关重要。这一发现获得了1995年的诺贝尔医学奖。此外，超过75%的已被确定为导致人类疾病的基因也存在于苍蝇中。因此，苍蝇是一个很好的系统，可以进行详细的研究，这些研究结果最终可以从基础研究实验室转化为临床。