The Frazier lab investigates the function, structure and mechanism of thrombospondin-1 (TSP1) and its receptors, CD36 and CD47, formerly known as integrin-associated protein. TSP1 is the founding member of the TSP family of 5 genes and proteins that are implicated in vascular regulation and pathology. TSP1 is a multidomain, secreted protein that binds to many receptors and other secreted proteins.

CD36 has important roles in lipid uptake and metabolism, atherogenesis and innate immunity. We discovered that ligation of CD36 by TSP1, a TSP1 domain and peptides from that domain, inhibits angiogenesis. Using one of our TSP1 peptides as a lead compound, Abbot Laboratories has developed ABT-510, now in clinical trials as in anti-cancer drug.

Through CD47, TSP1 regulates the function of many vascular integrins by “inside-out” signaling through heterotrimeric Gi. CD47 can also activate β3 integrins by direct association in the plane of the membrane as demonstrated by αvβ3 activation by the extracellular IgV domain of CD47 anchored to the membrane by a GPI (lipid) tail. This work led us to discover a new mechanism of integrin activation.

Nitric oxide (NO) is a master regulator of cardiovascular physiology. Very recently, we discovered a completely unsuspected mechanism by which the TSP1-CD47 system regulates NO signaling in vascular cells. This important finding provides a unifying mechanism for the diverse effects of TSP1 and CD47 on endothelial and smooth muscle cells, platelets and leukocytes. It casts these proteins as important players in regulation of hemostasis, vessel tone, tissue perfusion, inflammation, atherosclerosis, restenosis and other physiological and pathological processes in which NO is an important modifier.