Document text
Principal Investigator: Margaret Lise Gardel
Organization: UNIVERSITY OF CHICAGO
Fiscal Year: 2024
Award: $393,173
Funding agency: National Institute of General Medical Sciences
Project Summary
Mechanisms of Mechanotransduction by LIM Domain Proteins
Mechanical forces are essential to controlling the shape, movement and even many
aspects of cell physiology. Changes in the environment mechanics or defects in cellular
mechanoresponse are implicated in a plethora of diseases including atherosclerosis,
heart failure and cancer. A major challenge is to understand mechanotransduction - the
mechanisms by which mechanical information is detected and communicated to
pathways that control cell behavior. The LIM super family of proteins, which contain one
or more LIM domains, represents a large number of putative mechanosensitive cellular
proteins that are involved in physiological mechanotransduction pathways.
Understanding how the LIM domains function to detect and transmit information about
mechanical stress will result in a deeper understanding of mechanotransduction-based
signaling, which is important for developing strategies of disease treatment and organ
regeneration.
This proposal leverages an innovative combination of cell biophysics, biochemistry
molecular cell biology, live cell imaging and mathematical modeling to investigate the
mechanism by which LIM domains sense mechanical stimuli in the actin cytoskeleton
and, in turn, initiate YAP/TAZ mechanotransduction signaling. We recently discovered
that a large number of LIM domains exhibit force-sensitive binding to actin filaments. Here
we propose to: (1) identify the mechanism by which LIM proteins are recruited to
mechanically stressed actin filaments, (2) determine how the LIM sequence enables
specificity in force-dependent recruitment within the actin cytoskeleton and (3) elucidate
how the mechanosensing by LIM protein LIMD1 initiates the YAP/TAZ
mechanotransduction pathway. These studies have the potential to demonstrate a highly
conserved mechanism of cell mechanosensing, and the methodologies will establish a
novel strategy for tackling cell mechanotransduction.
Terms: <Actin Filaments><Actins><Adherens Junction><Adhering Junction><Adhesion Plaques><Adhesive Junction><Affect><Affinity><Anchoring Junction><Apoptosis><Apoptosis Pathway><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Avidity><Binding><Biochemistry><Biological Chemistry><Biophysics><Body Tissues><CRR Domain><Cancers><Cell Body><Cell Communication and Signaling><Cell Function><Cell Growth in Number><Cell Multiplication><Cell Physiology><Cell Process><Cell Proliferation><Cell Signaling><Cell Size><Cell-Matrix Adherens Junctions><Cells><Cellular Function><Cellular Matrix><Cellular Mechanotransduction><Cellular Metabolic Process><Cellular Physiology><Cellular Process><Cellular Proliferation><Cellular biology><Collaborations><Communication><Comparative Study><Cues><Cysteine Rich Region><Cytoplasm><Cytoskeletal System><Cytoskeleton><Defect><Development><Disease><Disorder><Elements><Enigma Homolog><Environment><Epithelial Cells><Epithelium><Exhibits><Family><Focal Adhesions><Focal Contacts><Heart failure><Hydrophobicity><In Vitro><Intracellular Communication and Signaling><Investigation><Knowledge><LIM Domain><LIM Domain Protein><LIM Protein RIL><Malignant Neoplasms><Malignant Tumor><Mammalian Cell><Math Models><Measures><Mechanical Signal Transduction><Mechanical Stress><Mechanics><Mechanosensory Transduction><Methodology><Microfilaments><Modeling><Modernization><Molecular><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Monitor><Movement><Myofilaments><Organelles><Pathway interactions><Periodicals><Phenylalanine><Physiologic><Physiological><Physiology><Process><Programmed Cell Death><Protein Family><Proteins><Regulation><Reversion-Induced LIM Protein><Series><Shapes><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Sorting><Specificity><Stress><Stress Fibers><Subcellular Process><Surface><Testing><Tissues><Transmission><ZYX><ZYX gene><atheromatosis><atherosclerotic disease><atherosclerotic vascular disease><biological signal transduction><biophysical foundation><biophysical principles><biophysical sciences><body movement><cardiac failure><cell behavior><cell biology><cell metabolism><cellular behavior><cellular metabaolism><conformation><conformational><conformational state><conformationally><conformations><developmental><experiment><experimental research><experimental study><experiments><innovate><innovation><innovative><insight><intracellular skeleton><live cell image><live cell imaging><live cellular image><live cellular imaging><malignancy><mathematic model><mathematical model><mathematical modeling><mechanic><mechanical><mechanical cue><mechanical force><mechanical signal><mechanical stimulus><mechanosensing><mechanotransduction><multi-scale computational modeling><multi-scale mathematical modeling><multi-scale modeling><multidisciplinary><multiscale computational modeling><multiscale mathematical modeling><multiscale modeling><neoplasm/cancer><new approaches><novel approaches><novel strategies><novel strategy><organ regeneration><pathway><paxillin><periodic><periodical><reconstitute><reconstitution><recruit><transmission process><zyxin>