Fibrosis drives disease in many cardiovascular and dermatological conditions. Myhre syndrome
(MYHRS) is a Mendelian profibrotic disorder with progressive multisystem involvement, including
cardiovascular defects (aortic stenosis), a stiff and thickened skin, and musculoskeletal involvement.
Affected individuals may show intellectual disability and autism. MYHRS is caused by recurrent
pathogenic variants (PV) in SMAD4 conferring increased stability to SMAD4, a common mediator of
transforming growth factor β (TGFβ) and bone morphogenic protein (BMP) signaling. There is
currently no cure for this potentially life-threatening and underreported condition.
This project characterizes the consequences of MYHRS-associated SMAD4 PV in complementary
disease models, including fibroblast cultures, zebrafish, and 3D skin models. We will apply advanced
omic strategies to evaluate altered interaction partners and DNA binding of mutant SMAD4 and to
study profibrotic cellular signatures in the cardiovascular system and skin. We will perform wound
modeling to identify phenotype changes in crucial cells that form the ‘fibrotic niche’. We use state-ofthe-art imaging to identify early profibrotic readouts, and monitor cell-matrix interrelationships. This
project will deliver the profibrotic signatures in MYHRS and situates in a larger endeavor to
understand the role of the TGFβ and BMP signaling in vascular and dermal disease to formulate
disease modifying anti-fibrotic strategies.