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: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=739002
• 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，这些信息决定它们及其邻居的行为方式。为了实现这一目标，细胞必须不断地与它们的邻居、它们自己以及它们的环境进行对话。生物体依靠细胞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到其他细胞。传统上，我们的五种基本感官包括视觉、嗅觉、味觉、听觉和触觉，这些刺激如何被接收、如何进入细胞以及进入细胞后会发生什么，是研究信号转导的生物学家面临的主要问题。基础研究使人们更好地了解细胞如何接收信号并将信号传递到细胞中，但该领域的主要障碍是该信号如何触发细胞内多个（通常是不同的）信号通路。我们现在知道这些通路之间发生了大量的“串扰”，并且在这些交叉点上起作用的蛋白质控制着这些更大网络内移动的信息流。我的长期兴趣集中在高度进化保守且复杂的 Wnt 信号通路上，这些信号通路调节胚胎发育和成体组织维持的关键方面。有 19 种哺乳动物 Wnt 蛋白通过三个主要途径发出信号，每个途径都受到信号网络中其他途径的影响。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，并且可以很好地充当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 网络内的信号如何受蛋白质调节，以指导细胞在脊椎动物胚胎发育过程中采取新的命运。首先，我计划研究基因组的变化如何影响被认为调节 Wht-Hh 信号传导的候选蛋白的表达，然后直接编辑这些候选蛋白的基因组成，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。这些新信息将有助于更好地理解通信串扰，确保提供正确的信息流来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，我的学员将学习大量的软技能，并获得最先进技术的宝贵实践经验，这将使他们在未来的职业生涯中具有高度竞争力。