Fibrillin-1 regulation of TGFbeta bioavailability

Transforming growth factor (TGF) beta is a potent growth factor that regulates cell survival, proliferation, migration and differentiation. Understanding TGFbeta signalling dysregulation in severe heritable diseases such as Marfan syndrome, and in chronic fibrotic disorders such as sclerosis is a major challenge in the search for effective therapies. We have discovered that fibrillin-1 regulates TGFbeta1 bioavailability by releasing latent TGFbeta from the extracellular matrix. This application is to build on, and exploit our discovery that the extracellular matrix molecule fibrillin-1 regulates TGFbeta bioavailability. We will resolve the molecular basis of how fibrillins regulate TGFbeta, and how we can exploit this knowledge therapeutically. Outcomes will be new insights into how TGFbeta is regulated by the extracellular matrix, and new therapeutic strategies to regulate TGFbeta bioavailability in health and disease.

Transforming growth factor (TGF)beta is a potent growth factor that regulates cell survival, proliferation, migration and differentiation. Understanding TGFbeta signalling dysregulation in Marfan syndrome and related heritable diseases, and in chronic fibrotic disorders such as sclerosis is a major challenge in the search for effective therapies. We have discovered that fibrillin-1 regulates TGFbeta1 bioavailability by releasing latent TGFbeta from the extracellular matrix. This proposal is to resolve the molecular basis of how fibrillins regulate TGFbeta, and how to exploit this knowledge therapeutically.