Grant: Discovery Grants Program - Individual

Cell motility is of fundamental importance in development, immune surveillance, and wound healing in eukaryotes. It also plays a nefarious role in metastasis in cancer. The actin cytoskeleton, which shapes the cell and drives protrusive motility is regulated by layers of signaling pathways. A focal question that motivates my research is how spatio-temporal dynamics of such signaling molecules are coordinated, and how these then combine to produce directed cell motility. My work includes derivation and analysis of mathematical models (both detailed and simplified for analysis), simulations of the time behaviour and spatial distribution of intracellular signaling molecules, and experimental validation (with experimental collaborators).I plan to (1) further develop models for feedback between signaling proteins (Rho GTPases Cdc42, Rac, Rho), lipids (phosphoinositides PIP2, PIP3), and actin (2) validate such models in further rounds of microfluidic cell polarization experiments carried out by Andre Levchenko (J. Hopkins), (3) simulate the revised models in1D and in 2D cell motility computations (with Stan Maree and post-doctoral fellows), (4) develop new models for GTPase dynamics in cell division (with Karen Oegema), in structures such as invadopodia (with John Condeelis) , and in single-cell wounds (with W Bement), (5) further extend modeling techniques to GTPase signaling in the context of cofilin activation and a burst of protrusive activity in mammary carcinoma cells (with John Condeelis). HQP training will be involved in every aspect of the research.Mathematical modeling has emerged as an important tool in the service of cell biology. It can help to formalize and test hypotheses, to suggest and design new experiments, and to predict variables that are not easy to measure experimentally. My work uses modeling, analysis, computations, and detailed collaboration with experts that can supply data and carry out new experiments.