Cell Signaling in Embryonic Epithelial-to-Mesenchymal Transitions

胚胎上皮间质转化中的细胞信号转导

• 批准号: RGPIN-2014-03704
• 负责人: Kelly, Gregory
• 金额: $ 2.55万
• 依托单位: University of Western Ontario
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=587368
• 关键词: Cell; Signaling; Embryonic; Epithelial; Mesenchymal

Determining the intricacies of the numerous signal transduction events that go on within and between cells is one of the most actively investigated areas in the field of cellular and molecular biology. Basic biological research has led to important breakthroughs, which have been capitalized on by the pharmaceutical industry. Although that industry is focused on human health and disease and driven by profit, the overall importance of these signaling events must be underpinned by the fact that they are responsible for initiating, shaping and maintaining the life of every living organism, regardless of whether or not it has a backbone. Historically, these pathways were once naively thought to unfold in a linear fashion, but as more pathways and their protein participants were discovered it was realized that a significant amount of communication exists between them. This crosstalk at nodes where the pathways intersect has made the study of any one pathway in isolation obsolete, and thus their identification has garnered significant attention especially in the signal transduction field of developmental cell biology. My interests and that of many other labs in Canada and abroad lie with a group of 19 Wnt proteins and a much smaller, but just as influential group of three Hedgehog proteins, which drive several signaling pathways that contribute to the embryonic development of almost every animal on Earth. Fertilized eggs divide repeatedly to produce a pool of cells, which differentiate along specific paths if and only if they can correctly interpret the combination and levels of the Wnt and Hedgehog ligands presented to them. In some instances this interpretation leads to the transition of one cell type that had been firmly attached to a membrane and its neighbors, into another that is highly migratory and aggressive in its ability to colonize other regions of the embryo or body in the case of the adult. These transitions occur several times during embryogenesis, but most people are probably more familiar with those associated with metastatic cancer, where in many instances fully differentiated cells later in life are reprogrammed mistakably due to having again received the same Hedgehog or Wnt ligands. To further complicate our understanding of the signal transduction events that go on within and between embryonic cells, we and others have recently found that in the absence of a Wnt protein, highly reactive oxygen species naturally generated by living cells and at levels that are not dangerous to them, can prime the Wnt signaling pathway in preparation for its full activation by the ligand. In the example of the differentiated cells this ability to prime a signaling pathway could have dire consequences especially to those cells that have inadvertently retrieved a Wnt ligand. My objectives are to first determine how the Wnt and Hedgehog pathways are activated during mouse and zebrafish embryonic development and then uncover the extent of the signaling crosstalk between the pathways at specific times, and finally to identify how the node(s) or other proteins in the pathways are affected by reactive oxygen species. I am confident that attaining these goals will lead to a better understanding of the communication crosstalk that ensures the correct flow of molecular information is made available to instruct one cell type to adopt a new fate. Towards that end, I expect that the publications and presentations of this basic biological research will be of significant interest and applicable to many areas of what worldwide is presently and will continue to be, a high profile and highly competitive field of developmental, cell, molecular and chemical biology.

确定细胞内和细胞间发生的众多信号转导事件的复杂性是细胞和分子生物学领域最活跃的研究领域之一。基础生物学研究带来了重要的突破，这些突破已被制药工业所利用。尽管该行业专注于人类健康和疾病，并受利润驱动，但这些信号事件的总体重要性必须得到这样一个事实的支持：它们负责启动、塑造和维持每一个生物体的生命，而不管它是否有主干。从历史上看，这些途径曾经被天真地认为是以线性方式展开的，但随着更多的途径和它们的蛋白质参与者被发现，人们意识到它们之间存在着大量的交流。这些通路相交节点上的串扰使得单独研究任何一条通路都变得过时，因此它们的鉴定引起了极大的关注，特别是在发育细胞生物学的信号转导领域。我以及加拿大和国外许多其他实验室的兴趣在于一组19种Wnt蛋白和一组小得多但同样有影响力的3种Hedgehog蛋白，它们驱动几种信号通路，对地球上几乎所有动物的胚胎发育都有贡献。受精卵反复分裂产生一个细胞池，当且仅当它们能够正确地解释呈现给它们的Wnt和Hedgehog配体的组合和水平时，这些细胞沿着特定的路径分化。在某些情况下，这种解释导致一种细胞类型的转变，这种细胞类型已经牢固地附着在膜上及其周围，而另一种细胞类型具有高度迁移和侵略性，能够在胚胎或成人身体的其他区域定居。这些转变在胚胎发生过程中发生多次，但大多数人可能更熟悉与转移性癌症相关的转变，在许多情况下，在生命后期完全分化的细胞由于再次接受相同的Hedgehog或Wnt配体而被错误地重新编程。为了进一步使我们对胚胎细胞内部和胚胎细胞之间的信号转导事件的理解复杂化，我们和其他人最近发现，在缺乏Wnt蛋白的情况下，活细胞自然产生的高活性氧，在对它们无害的水平上，可以启动Wnt信号通路，为其被配体完全激活做准备。在分化细胞的例子中，这种启动信号通路的能力可能会产生可怕的后果，特别是对于那些无意中恢复了Wnt配体的细胞。我的目标是首先确定Wnt和Hedgehog通路在小鼠和斑马鱼胚胎发育期间是如何被激活的，然后揭示特定时间通路之间信号串扰的程度，最后确定通路中的节点或其他蛋白质如何受到活性氧的影响。我相信，实现这些目标将导致更好地理解通信串扰，确保分子信息的正确流动，以指导一种细胞类型采用新的命运。为了实现这一目标，我希望这一基础生物学研究的出版物和报告将引起人们的极大兴趣，并适用于全球目前和将来的许多领域，这是一个引人注目和高度竞争的发育、细胞、分子和化学生物学领域。