Grant: Discovery Grants Program - Individual

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.