Paul B. Yu, MD, PhD
Year elected: 2018
Current membership category: Active
Brigham & Women’s Hospital, Harvard Medical School
20 Shattuck Street, Thorn Biosciences 1219
Boston, MA 02115
United States of America
Our work seeks to understand the roles of bone morphogenetic protein (BMP) and TGF-beta signaling in development, physiologic homeostasis, and disease. We have probed this signaling pathway in pulmonary vascular disease, heterotopic ossification (HO), anemia and iron metabolism, vascular calcification, and cancer biology, using progenitor cell biology, small molecule, and other pharmacologic approaches. We and collaborators reported the first selective inhibitors of BMP type I receptor kinases, and explored their therapeutic potential in pre-clinical models of the congenital HO syndrome fibrodysplasia ossificans progressiva (FOP) and anemia of inflammation. We have pursued the mechanisms by which combinatorial specificity and signal activation are regulated in this pathway. The requirement for Activin and BMP type II receptors ACVR2A/BMPR2 for mediating the dysregulated signaling of mutant ALK2 in FOP anticipated the identification of activin A signaling as the pathogenetic driver of FOP. Our studies on defective BMP signaling in pulmonary arterial hypertension (PAH) implicated the loss of BMP9 signaling in certain acquired forms of PAH, and therapeutic potential of modulating BMP9 signaling. Our goals are to understand how this pathway achieves contextual specificity in developmental patterning and pathophysiologic remodeling, and to define the circumstances under which it is therapeutically tractable.