BBB seminar: Dean Sheppard
Targeting integrin-mediated TGFβ activation to treat asthma, multiple sclerosis, acute lung injury and organ fibrosis
Lung Biology Center and Department of Medicine, University of California San Francisco (UCSF), CA, USA
Integrins are a family of hetodimeric transmembrane receptors that recognize a wide variety of spatially restricted extracellular and cell-surface ligands. Because of their tight linkage to the actin cytoskeleton, integrins play important roles in both responding to and generating mechanical force. We have found that three integrins (αvβ1, αvβ6 and αvβ8) recognize stored latent forms of the growth factor, transforming growth factor β (TGFβ) as their principal in vivo ligand and that these integrins play a critical role in activating TGFβ in distinct biological contexts, a process that depends on mechanical deformation of the tethered latent growth factor. Using constitutive or conditional knock-out mice, blocking antibodies and small molecule inhibitors we have developed a means to target these integrins, and we have identified important roles for this process in murine models of asthma, multiple sclerosis, acute lung injury and tissue fibrosis. The effectiveness of therapeutic interventions inhibiting these integrins suggests that some or all might be promising targets for improved treatments of these diverse diseases. Because each integrin only activates TGFβ in distinct contexts, this approach is likely to be safer than directly inhibiting the growth factor or its signaling receptors.
Chairperson: Donald Gullberg, Department of Biomedicine