Mapping cell signaling crosstalk in differentiation and development.

细胞被认为是生命的基本膜单位，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方式。为了实现这一点，细胞必须不断地与它们的邻居、自己和环境交谈。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，这些刺激是如何接收的，它们如何进入细胞，以及一旦进入细胞内发生了什么，这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了细胞如何接收信号并将其传递到细胞内，但该领域的一个主要障碍是该信号如何在细胞内触发多个通常是不同的信号通路。我们现在知道，在这些通路之间会发生大量的“串扰”，在这些交叉点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信号通路上，该信号通路调节胚胎发育和成年组织维持的关键方面。哺乳动物有19种Wnt蛋白，它们通过三条主要途径传递信号，每条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，它们也使用自己进化上保守的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，包括在两者之间共享的蛋白质，并且处于很好的位置来作为调节器来控制网络中的信息流。我的目标是确定这些WNT-HH网络中的信号是如何由蛋白质调节的，以便指示细胞在脊椎动物胚胎发育期间采用新的命运。首先，我计划研究基因组的变化如何影响被认为调节Wht-HH信号的候选蛋白质的表达，然后直接编辑这些候选蛋白质的基因构成，以确定它们在细胞间通信中的作用。接下来，我将确定新的调节器，然后将实验转移到整个动物系统，并展示扰乱这些蛋白质的活动如何影响发育。这一新信息将导致对通信串扰的更好理解，以确保提供正确的信息流来改变任何小区的行为。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，我的受训人员将学习到许多软技能，并获得宝贵的最新技术实践经验，这将使他们在未来的职业生涯中具有很强的竞争力。

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.