Cells sense extracellular matrix (ECM) stiffness and physical forces applied through the ECM through integrin-mediated adhesions. These mechanotransduction processes play critical roles in embryonic development, normal physiology and multiple diseases, including cancer, hypertension, atherosclerosis and fibrosis among others. However, mechanical responses differ between cell types, between the same cell type in different states, and even in different regions of single cells. While much has been learned about mechanotransduction through integrins, a major area of ignorance is how different types and components of matrix adhesions modulate cell responses to force.
The aim of this project is therefore to characterize the mechanosensing properties of distinct types and compositions of integrin mediated adhesions and elucidate the molecular basis for these differences. A major limitation in our current understanding of mechanosensing by different types of adhesions is that current, morphology-based classifications into nascent, focal or fibrillary adhesions or focal complexes are imprecise, with little information about composition or structure. Additionally, adhesions in cells continuously evolve, so that actual adhesions are often mixtures of different types. Recent work has now defined specific molecular complexes that serve as modules for construction of different adhesion classes. Indeed, the data argue that adhesions have a modular structure with these protein complexes serving as the core modules that are combined and modified to generate diversity. Based on this hypothesis, we will: 1.Combine biochemical approaches with novel imaging and machine learning methods to elucidate the composition and behaviors of the distinct adhesion modules. 2.Utilize these biochemical and imaging methods in conjunction with assays of cytoskeletal and adhesion dynamics and tension to characterize the cytoskeletal organization and dynamics for the distinct adhesion complexes. 3.Combine novel imaging and engineering approaches to characterize the distinct signaling properties of the different adhesion states and their responses to substrate stiffness and applied strain.
Integrin mediated adhesions sense the mechanical properties of and forces applied through the extracellular matrix. A major area of ignorance in this field is how different types of adhesions differentially respond to mechanical information. One reason for this problem is our limited current understanding of the composition and structure of different types of adhesions. This multi-PO project will combine highly novel biochemical, imaging and image analysis, force measurement, mechanotransduction and signaling methods to develop a deeper understanding of the composition and structure of different adhesion types, and apply this information to understanding their cytoskeletal dynamics and mechanotransduction properties.
Showing the most recent 10 out of 48 publications
