CAREER: Actin Cytoskeleton Biomechanics and Mechanobiology in Complex Cellular Environments

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This Faculty Early Career Development (CAREER) grant will support an interdisciplinary research and education program to investigate the fundamental roles of the actin cytoskeleton. The actin cytoskeleton is an essential structural component of a living cell and exists in a complex environment. Changes in actin mechanics and structure occur in response to environmental stresses such as crowding. These changes are linked to cell physiology and disease states. The PI and research team will use protein biophysics and nanoscale tools to measure how the mechanical and structural properties of the actin cytoskeleton change with crowding. The knowledge gained will impact a broad range of applications in multiple scientific fields including cell physiology and aging. Integration of the research findings to a uniquely designed biophysics pedagogy will benefit undergraduate and graduate students at the University of Central Florida (UCF). Educational materials will be developed for STEM education of K-12 students and outreach activities for general public. Through this project, the PI will recruit and train underrepresented minority students at UCF as well as from local community colleges. The PI will also mentor young female scientists to foster their interests and careers in STEM. These efforts will contribute to a more diverse scientific workforce.Actin assembly drives many important cellular processes, which take place in a crowded and confined cytoplasm. Despite increased appreciation of macromolecular crowding effects, it is not well established how crowded intracellular environments, along with altering ionic and osmotic conditions, modulate cytoskeletal filament mechanics and structure. The goal of this CAREER project is to identify molecular mechanisms by which varying intracellular environments modulate the conformations, mechanics, and mechanosensing of actin cytoskeleton. The central hypothesis is that changes in filament mechanics and conformations induced by crowding or osmotic stress affect interactions with actin binding proteins, which in turn can alter cellular mechanics and physiology. To prove the hypothesis, the work will 1) determine how mechanics and conformations of actin filaments and crosslinked bundles are modulated in crowded environments at the nanoscale, 2) evaluate filament assembly dynamics and interactions with actin crosslinking proteins in crowded environments, and 3) determine how actin cytoskeleton responds to geometric constraints, mechanical forces, and cellular environmental factors, in addition to osmotic stress. By combining molecular biophysics and state-of-the-art nanoscale characterization, this work will transform the understanding of cell physiology and disease states in terms of the mechanisms that control the physicochemical, mechanical, and structural properties of actin cytoskeleton.The Molecular Biophysics cluster of the Division of Molecular and Cellular Biosciences provided cofounding for this award.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.