Development of Mouse Models to Study the Role of Mechanotransduction in Disease Pathogenesis

About This Grant

Summary The ability of a cell to sense, integrate, and convert mechanical stimuli into biochemical signals that result in intracellular changes is called mechanotransduction. Defects in mechanotransduction are implicated in the pathogenesis of various diseases, including arteriosclerosis, cardiomyopathies, asthma, and cancer. Thus, therapeutic means of manipulating mechanotransduction to restore mechanical homeostasis in diseased tissue represent a novel approach to treating various diseases. The goal of this R21 application is to develop a series of novel mechanotransduction-defective mouse strains that the research community can apply to multiple diseases. Vinculin, a cytoskeletal adaptor protein, plays a central role in sensing mechanical stress and mediating structural remodeling and functional responses within the cell. Site-specific tyrosine phosphorylation of vinculin has been proposed to regulate its mechanical role at both cadherin and integrin adhesions. We hypothesize that vinculin phosphorylation regulates the mechanical response of tissues to increase forces by adjusting the balance between cell-cell and cell-extracellular matrix (ECM) adhesions. This R21 proposal seeks to develop and validate a series of point mutations that alter posttranslational modification of vinculin in mice, thus allowing investigation of vinculin mechanosensing in physiology and disease. The following interrelated aims are proposed: (1) To test the hypothesis that tyrosine phosphorylation (Y822) of vinculin coordinates the mechanical response of cell adhesion structures. (2) To test the hypothesis that vinculin phosphorylation (Y100/Y1065) is required to facilitate cell-ECM interactions. Due to the vast effects of mechanobiology on disease pathogenesis, our innovative mouse models are anticipated to be widely used by scientists in an array of fields and, therefore, of relevance to multiple NIH Institutes.