Project Summary The important challenge this project addresses is to gain a mechanistic understanding of regulatory elements that tightly control the spatiotemporal dynamics of intracellular signaling pathways. To meet this challenge, we combine computational approaches, including mathematical modeling and image analysis, with experiments performed at the single cell level. All cells must sense and respond to changes in their environment. Environmental cues such as hormones, nutrients or physical stresses are detected by receptors on the cell surface. This information is than processed and transmitted to appropriate regions of the cell by intracellular signaling pathways. The proper response to a stimulus often requires cells to change shape or move. Therefore, signaling pathways must coordinate the dynamics of the actin cytoskeleton in both space and time. This task is accomplished through the use of feedback and feedforward loops acting over multiple temporal and spatial scales. Because these regulatory loops make signaling pathways inherently nonlinear, mathematical modeling is required to understand the emergent properties of these systems. We have identified three cellular processes that lend themselves to systems-level analysis and form the basis for our studies over the next five years: 1) directed growth during mating and budding in the yeast S. cerevisiae and related fungi, 2) phagocytosis, the process through which cells sense and ingest bacteria and other objects, and 3) collective migration in which a group of cells move as a single unit. These projects represent the continuation of established collaborations and exciting new directions for my lab. We will continue our collaboration with the lab of Dr. Daniel Lew (Duke, Pharmacology and Cancer Biology) to understand the mechanisms that underlie polarity establishment and gradient sensing in S. cerevisiae. In a new collaboration with Dr, Amy Gladfelter (UNC, Biology), we will investigate if similar mechanisms play a role in the establishment of multiple polarity sites by the fungus Aureobasidium pullulans. We also will continue our long-standing collaboration with the lab of Dr. Klaus Hahn (UNC, Pharmacology) to investigate the mechanisms that underlie spatial patterning during phagocytosis. Finally, we have recently established a new collaboration with Dr. Scott Magness (UNC, BME) to investigate epithelial polarization during collective migration. The goal of our investigations is to generate truly predictive models of in vivo cellular processes that ultimately provide insights into the etiology and treatment of human diseases.

Narrative The goal of this project is to combine mathematical modeling with quantitative experimental approaches to understand the feedback and feed forward loops that regulate intracellular signaling networks. In human cells, dysregulation of these networks leads to many diseases, including cancer and heart disease. The ultimate goal of this project is the development of predictive models of in vivo cellular processes that can be used in the rational design of therapeutic strategies for treating disease.