Our laboratory is interested in the characterization of the multiple roles that the extracellular matrix plays during vertebrate organogenesis, and in congenital and acquired disorder of the connective tissue. We are currently focused on the characterization of pathophysiological mechanisms in Marfan syndrome and scleroderma using a combination of in vivo and ex vivo approaches. Our long-term goal is to identify suitable biological targets for therapeutic interventions against these life-threatening diseases.
Marfan syndrome is a common disorder of the connective tissue caused by mutations in fibrillin-1, the main structural component of extracellular microfibrils. We have shown that multisystem manifestations in Marfan syndrome are accounted for by the combined effects of impaired tissue integrity and promiscuous activation of TGF-β signals. We are studying the mechanisms whereby fibrillin-rich microfibrils regulate local TGF-β signals, and how dysregulation of this key function impairs morphogenesis and tissue homeostasis.
Excessive deposition of a disorganized collagen matrix resulting in loss of organ function is the hallmark of clinically distinct fibrotic conditions. Recent studies have implicated Ras stabilization by reactive oxygen species (ROS) in promoting and/or sustaining skin fibrosis in scleroderma. We are investigating the intracellular events downstream of the ROS/Ras loop leading to collagen up-regulation, as well as the functional relationship between the ROS/Ras and TGF-β signaling pathways in fibrogenesis.