Actin cytoskeleton organization and function in health and disease

The National Institute of General Medical Sciences awarded The Ohio State University $441,570 on May 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to explore actin cytoskeleton organization and function in health and disease. The project runs through April 30, 2031, with performance at Columbus, Ohio.

The research advances understanding of how actin-binding proteins called plastins organize actin filaments into higher-order assemblies—bundles and networks—and examines their roles in normal cellular processes including cytokinesis, migration, and membrane protrusion stabilization, as well as their contribution to pathology in carcinogenesis, neurodegeneration, hereditary diseases, and infectious disease. A second research direction investigates how bacterial pathogens produce actin-targeting effectors that disrupt and usurp the actin cytoskeleton to compromise cell morphology, motility, phagocytosis, epithelial permeability, and antigen presentation. The work is intended to advance human health by clarifying the molecular and cellular mechanisms underlying actin cytoskeleton regulation and its dysfunction in disease states including congenital disease and metastatic cancer.

Abstract

The overarching goal of this proposal is to explore novel aspects of the actin cytoskeleton organization and function in health and disease. The remarkable functional versatility of the actin cytoskeleton stems from its ability to assemble into a variety of diverse structures - branched networks/meshes and aligned bundles. This architectural complexity is orchestrated by actin-binding proteins, whose activity is delicately regulated in response to internal and external signals. Human plastins are versatile actin-binding proteins that organize actin filaments into higher-order assemblies: bundles and networks. Plastins are involved in cytokinesis, migration, and stabilization of membrane protrusions, but also in the pathogenesis of the following diseases: carcinogenesis, neurodegeneration, and hereditary and infectious diseases. Despite the importance and long- lasting interest of the research community in these proteins, understanding of their interaction with actin and their regulation is superficial. Our first research direction is to contribute to human health and well-being by advancing the understanding of the actin cytoskeleton organization by actin-bundling proteins plastins and their contribution to pathologies (e.g., congenital diseases and metastatic cancers) at the molecular and cellular levels. Playing numerous vital roles in human defense mechanisms, the actin cytoskeleton is a common target for numerous bacterial pathogens, which developed various elegant and sophisticated ways to disrupt and usurp IT by producing actin-targeting effectors. By hijacking the actin cytoskeleton, pathogenic toxins disturb cell morphology, cell motility, phagocytosis, epithelial permeability, and antigen presentation. Being constantly adjusted to the host cytoskeleton by CO-evolution, they recognize weaknesses in the host defense and represent powerful tools that foster the understanding of the cytoskeleton on molecular and cellular levels. The urge for a thorough understanding of bacterial pathogenicity is further necessitated by the dissemination of multidrug- resistant pathogens that undermine the efficiency of antibiotics. The second research direction of this proposal is to decipher the in-depth molecular and cellular mechanisms of bacterial effectors targeting the actin cytoskeleton to i) enable alternative ways of targeting pathogens and II) get a deeper understanding of the actin cytoskeleton per SE. The current proposal is directly relevant to the NIH mission as IT focuses on three families of bacterial effectors, all produced by human pathogens: vibrio cholerae and vibrio parahaemolyticus vopf/vopl (1) and vopm/vopv (2), and legionella pneumophila mavh, ravh, and vipa (3). Furthermore, the proposal is of interest for a general understanding of human physiology as each of the above toxins reveals novel properties of the actin cytoskeleton. Finally, the understanding of the molecular and cellular mechanisms governing the function of actin-bundling proteins plastins contributes to explaining the pathology of plastin-related human diseases.