The individual cells of multicellular organisms sense chemical signals that are essential both to maintain the organisms and to enable them to respond to changes in the environment. Cells have developed complex biochemical events (signaling) that allow them to sense very subtle changes in the concentration of these chemical signals (gradients). The PI uses yeast cells as a model to study these signaling events, but they are likely broadly applicable to cells in more complex organisms as well. In previous studies, he identified a variety of biochemical events that are required for cells to interpret chemical gradients. In this project, he will investigate the contributions of two novel signaling events, using the classic tools of cell biology, molecular genetics, molecular biology, biochemistry, and imaging. In addition, the PI will develop a mathematical model that not only describes the known components of the signaling system, but also predicts novel components of the pathway. This approach is particularly exciting because it will allow the PI to identify signaling events that might not have been identified through experimentation alone. In short, this project will work at the interface of mathematics and biology to identify the critical regulators of cells' responses to the chemical signals that allow them to function appropriately. The PI is committed to science education at all levels and will use the project to train undergraduates and students in an AP biology class. Every other year, the PI will offer his newly developed graduate seminar course, "Explaining Science" designed to teach graduate students how to talk about their work with anyone, from a child to a congressperson. The project will give the PI's students and postdoc the chance to work with collaborators who are experts in diverse areas. Because the project is at the interface of math and biology, researchers in each discipline will gain a better understanding of how those in the other discipline think.
Chemotropism, directed cell growth in response to a chemical gradient, is integral to axon guidance, angiogenesis, pollen tube guidance, and fungal infection. Naturally occurring chemical gradients are very shallow and dynamic. Models of chemotactic phenomena invoke positive feedback loops that amplify small differences in receptor activation across the cell surface into a substantially steeper intracellular signaling gradient. It is presumed that the response of chemotropic cells to shallow chemical gradients is also amplified by interacting feedback loops, but a mechanistic understanding of such loops is lacking. The goal of this project is to understand how the chemotropic growth site is established upstream of directed secretion, and how the cell responds to changes in the gradient after initial orientation. Observations made during the current project suggest that two interconnected positive feedback loops underlie the establishment of receptor polarity upstream of directed secretion. A mathematical reaction/diffusion model of these mechanisms has been developed, and will be used in combination with experimental approaches to provide a better understanding of how gradient-aligned receptor polarity is established and maintained. The degree to which the model mimics the behavior of gradient-stimulated yeast cells will guide both experimentation and the evolution of the model itself. This project will lead to a deeper and more comprehensive understanding of gradient sensing while simultaneously developing mathematical modeling as a tool for biologists. During this project period, the PI will continue to administer and train students in the NSF-Capstone Undergraduate Research Program, which he co-developed. He has also developed a graduate course, "Explaining Science", designed to teach graduate students how to explain their science to laypersons. He will meet annually with a high school AP biology class to discuss his research. The project will provide the PI's students and postdoc with interdisciplinary training, through interactions with collaborators who are experts in diverse areas. Specifically, the project is at the interface of math and biology and will provide students and postdoctoral researchers with training in this emerging area.
This project is funded jointly by the Cellular Dynamics and Function Cluster in the Molecular and Cellular Biosciences Division and by the Mathematical Biology Program in the Division of Mathematical Sciences.
