Talin dependent mechanical imprinting as driver for cardiac disease progression

Heart failure is a major cause of death. Mechanical signalling, initiated from extracellular matrix adhesions is critically involved in the disease progression.

Additionally, our data indicates that mechanical information can be stored or imprinted via post-translational modifications (PTMs) of the core adhesion protein talin.

These force-dependent modifications alter competitive interactions of talin binding partners that can give rise to long-lasting force-independent changes.

Accordingly, we hypothesise that mechanical imprinting in response to perturbed mechanical signalling can, over time, lead to abnormalities that persist even after correction of the initial defect (e.g. after treatment of fibrosis).

We will investigate this hypothesis at the 1) molecular scale, using optical trapping and single molecule binding/competition studies in presence/absence of force, as well as complementary biochemical experiments; 2) cellular scale, to investigate interactions/competition/PTMs at defined adhesions using bionanoarrays; and 3) tissue scale, to identify imprinting patterns in human heart biopsies and recapitulate them in engineered heart tissues – which allow us to employ targeted genome manipulation to alter and direct the mechanical imprinting and measure the larger-scale implications on cardiac function.

By iterating dynamically between these scales we will establish a predictive framework for mechanical imprinting that can be used to better understand heart disease.