Mapping cell signaling crosstalk in differentiation and development.

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和它们的邻居的行为。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对话。生物体依靠细胞来接收和解释大量的感官信息，然后，如有必要，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，而这些刺激是如何被接受的，它们是如何进入细胞的，以及进入细胞后发生了什么，是研究信号转导的生物学家面临的主要问题。基础研究已经让我们更好地理解细胞是如何接收并将信号传递到细胞内的，但是这个领域的一个主要障碍是这个信号是如何触发细胞内多个不同的信号通路的。我们现在知道，大量的“串扰”发生在这些途径之间，在这些交叉点服务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和复杂的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。哺乳动物有19种Wnt蛋白通过三种主要途径发出信号，每一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年细胞发出信号。Wnt和Hh通路有许多相似之处，包括两者之间共享的蛋白质，以及作为控制网络中信息流动的调节器的良好位置。我的目标是确定这些Wnt-Hh网络中的信号是如何被蛋白质调节的，以指导细胞在脊椎动物胚胎发育过程中采用新的命运。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-细胞通信中的作用。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动如何影响发育。这一新信息将有助于更好地理解通信串扰，从而确保正确的信息流可用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，我的学员将学习许多软技能，并获得宝贵的实践经验，最先进的技术，这将使他们在未来的职业生涯中具有很强的竞争力。

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.