Grant: Operating Grant

Fibrosis is a major cause for heart failure and death with no effective therapies available to date. When an infarct destroys parts of the heart muscle, connective tissue fibroblasts are activated into myofibroblasts (MFs) to repair the damage. They start secreting large amounts of fibrous collagen to glue the intact parts of the heart muscle together. Frequently, heart repair does not end and fibrous collagen accumulates to a stiff fibrotic scar. The scar hinders electrical transmission between heart muscle cells, mechanically obstructs the pumping function of the heart, and reduces its distensibility. Worse, the stiffness of the scar itself turns healthy cells into cells that will foster the stiffening process, ultimately leading to heart failure. It is our objective to stop MF activation by blocking mechanical activation of TGF-beta1, the most potent pro-fibrotic growth factor known. We have discovered that MFs pull TGF-beta1 out from stores in the extracellular matrix, literally like candy out of a wrapper. Liberated TGF-beta1 stimulates more MFs. To prevent vicious cycle, we will interfere with unique proteins, called integrins that MFs use as a handle to pull. We have already identified the integrins possibly activating TGF-beta1 in cardiac MFs. We will now test how cell force and matrix stiffness control their efficacy to activating TGF-beta1 using a variety of biomechanical assays. Using an animal model of heart fibrosis, we will test the importance of our integrin candidates by turning them on and off with molecular biology and specific drugs. Generally inhibiting TGF-beta1 in clinical strategies is impossible, because TGF-beta has many beneficial actions, such as reducing inflammation, regulating blood vessel growth and preventing tumour formation Our approach specifically addresses MF integrins to prevent TGF-beta activation. Other cells, using other mechanisms to activate the factor will not be affected.