Mapping cell signaling crosstalk in differentiation and development.

绘制分化和发育过程中细胞信号串扰的图谱。

• 批准号: RGPIN-2019-06610
• 负责人: Kelly, Gregory
• 金额: $ 3.06万
• 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: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=715207
• 关键词: Mapping; cell; signaling; crosstalk; differentiation

Cells are considered the fundamental membrane-bound unit of life and one of their basic functions is to send and receive a variety of information that dictates how they and their neighbors behave. To achieve this, cells must continually talk with their neighbors, to themselves, and with their environment. Organisms rely on cells to receive and interpret a multitude of sensory information and then, if necessary, output this data to other cells. Traditionally, our five basic senses include sight, smell, taste, hearing and touch, and how these stimuli are received, how they enter the cell, and what happens once inside are major questions facing biologists studying signal transduction. Basic research has led to a better understanding of how cells receive and relay a signal into the cell, but a major impediment in the field has been how this signal triggers multiple, often disparate signaling pathways within the cell. We now know that an extensive amount of “crosstalk” occurs between these pathways, and that proteins serving at these intersection points control the flow of information moving within these larger networks. My long-term interest has focused on the highly evolutionarily-conserved and complex Wnt signaling pathways that regulate key aspects of embryonic development and maintenance of adult tissues. There are nineteen mammalian Wnt proteins that signal through three main pathways, each of which are influenced by other pathways in signaling networks. Within these networks are three Hedgehog (Hh) proteins, which also use their own evolutionarily-conserved pathways to signal to embryonic and adult cells. The Wnt and Hh pathways possess many similarities, including proteins that are shared between the two, and well placed to serve as regulators to control the information flowing in the network. My goal is to determine how signaling within these Wnt-Hh networks is regulated by proteins in order to instruct cells to adopt new fates during vertebrate embryonic development. To begin, I plan on examining how changes to the genome influence the expression of the candidate proteins believed to regulate Wht-Hh signaling, then directly edit the genetic makeup of these candidates to determine their role in cell-cell communication. Next, I will identify new regulators and then move experiments into a whole animal system and show how disrupting the activity of these proteins affects development. This new information will lead to a better understanding of the communication crosstalk that ensures the correct flow of information is made available to change the behavior of any cell. Our publications will be impactful to many areas of biology, and as important, my trainees will learn numerous soft skills and gain valuable hands-on experience with state-of-the-art techniques, which will make them highly competitive in their future careers.

细胞被认为是生命的基本膜结合单位，它们的基本功能之一是发送和接收各种信息，这些信息决定了它们及其邻居的行为。为了实现这一点，细胞必须不断地与它们的邻居、它们自己以及它们的环境交谈。生物体依靠细胞来接收和解释大量的感官信息，然后在必要时将这些数据输出给其他细胞。传统上，我们的五种基本感觉包括视觉，嗅觉，味觉，听觉和触觉，以及这些刺激如何被接收，它们如何进入细胞，以及一旦进入细胞会发生什么，是研究信号转导的生物学家面临的主要问题。基础研究已经使人们更好地理解了细胞如何接收信号并将其传递到细胞中，但该领域的一个主要障碍是这种信号如何触发细胞内多种通常不同的信号通路。我们现在知道，在这些通路之间发生了大量的“串扰”，并且在这些交叉点处服务的蛋白质控制着在这些更大的网络中移动的信息流。我的长期兴趣集中在高度进化保守和复杂的Wnt信号通路，调节胚胎发育和成人组织维持的关键方面。有19种哺乳动物Wnt蛋白通过三种主要途径发出信号，每种途径都受到信号网络中其他途径的影响。在这些网络中有三种Hedgehog（Hh）蛋白，它们也使用自己的进化保守途径向胚胎和成体细胞发出信号。Wnt和Hh通路具有许多相似之处，包括两者之间共享的蛋白质，并且很好地作为调节器来控制网络中的信息流动。我的目标是确定这些Wnt-Hh网络中的信号传导如何受到蛋白质的调节，以指导细胞在脊椎动物胚胎发育过程中采用新的命运。开始，我计划研究基因组的变化如何影响被认为调节Wht-Hh信号的候选蛋白质的表达，然后直接编辑这些候选蛋白质的遗传组成，以确定它们在细胞间通讯中的作用。接下来，我将确定新的调节因子，然后将实验转移到整个动物系统中，并展示破坏这些蛋白质的活性如何影响发育。这一新信息将使我们更好地理解通信串扰，从而确保正确的信息流可用于改变任何细胞的行为。我们的出版物将对生物学的许多领域产生影响，同样重要的是，我的学员将学习许多软技能，并通过最先进的技术获得宝贵的实践经验，这将使他们在未来的职业生涯中具有很强的竞争力。