ACTIN ASSEMBLY AND CELL MOTILITY: MECHANISMS AND REGULATION

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Research Plan Summary / Abstract from Parent Grant (R35 GM118171) Our lab studies molecular and cellular mechanisms for actin assembly and actin-based cell motility. We want to understand how actin filaments assemble, how they interact with other cytoskeletal components and membranes, and how these interactions dictate cell shape and movement. The MIRA goals are: 1) combining existing grants, 2) promoting flexibility in new research directions, and 3) promoting stability and mentoring. 1) Existing Grants. “Mechanisms for Transendothelial Migration” is the current title of a long- standing grant focused on actin assembly and membranes. Transendothelial migration is a new area for us, one that emerged from studies on how NK cells migrate, find and kill their target cells. We are interested in how immune and cancer cells cross the endothelium of the vasculature during physiological and pathological processes. The migrating cell and the endothelial cell both actively participate, changing shape and exerting force as a result of actin filaments interacting with the plasma membrane and intracellular membranous organelles. “Regulation of Actin Capping Protein” is the current title of a newer grant focused on novel mechanisms of regulation of actin capping protein. Capping protein is a key regulator of the availability and activity of actin-filament barbed ends. Recent discoveries of novel regulators of capping protein have revealed unexpected insights that dramatically change our view of actin assembly in cells. We now know that regulators target capping protein to sites where cells need to assemble actin filaments and that they tune its filament-capping activity to a level that is physiologically relevant for the concentrations of the reactants and kinetics of the reactions. 2) Flexibility and New Research Directions. I have been successful in pursuing new directions, using new experimental systems, and adapting to new technologies, as described in my Biosketch. New areas for our lab in this proposal include novel connections between cytoskeleton filament systems, the use of zebrafish as a vertebrate model system, light-induced control of protein activity, and super- resolution correlative light and electron microscopy. 3) Mentoring and Stability. The MIRA FAQ mentions “more time for conduct of research and mentoring junior scientists in a more stable environment,” which resonates strongly with me. I enjoy serving as a mentor, and I am very proud of the success of our lab trainees and my faculty colleagues, within and outside of our department. In terms of stability, while we are grateful for our success in securing continued funding for our research, our ability to make transitions and explore new directions will be made more facile and efficient by the MIRA mechanism. 1