Joanne E. Murphy-Ullrich, PhD
Dept. of Pathology and Cell Biology
Division of Molecular and Cellular Pathology
Marquette University, Milwaukee, WI
University of Wisconsin, Madison, WI
PhD, Pathology, 1983
University of Wisconsin, Madison, WI
Postdoctoral Fellow, Depts. of Medicine and Physiological Chemistry, 1983-6
University of Alabama at Birmingham
Sr. Research Associate, Dept. of Biochemistry, 1986-8
Our research seeks to understand how the extracellular environment—matrix molecules and growth factors—regulate cellular processes such as growth, death, motility, and differentiation. We focus on a complex protein thrombospondin 1 (TSP1) which is made by cells in response to injury and stress.
Our lab was the first to identify TSP1 as one of a group of proteins that alters cell interactions with its matrix through stimulate of a state called “intermediate cell adhesion” characterized by loss of focal adhesions and altered actin cytoskeletal organization. It potentially acts as an “environmental adaptor” that enables a cell to respond to insults by altering its transcriptional program and its ability to move and survive. Such mechanisms are critical for wound repair and responses to injury: TSP1 binds to a cell surface receptor co-complex of calreticulin-LRP1 which signals increased cell motility and resistance to anchorage-independent apoptosis. These data suggest that TSP1 expressed during injury and repair or tumor stromal cells might affect persistence of myofibroblasts, thus contributing to repair, fibrosis, and altered tumor stroma. In vivo studies with the calreticulin binding sequence of TSP1 show that expression of this sequence of TSP1 stimulates collagenous capsule formation in a model of the foreign body response. In vitro studies suggest that TSP1 signaling through calreticulin-LRP1 modifies the foreign body responses by stimulating increased collagen matrix formation by activated fibroblasts. These studies have also identified calreticulin as a novel component of the extracellular matrix in injured arteries and in wounds, suggestive of a role for calreticulin in matrix remodeling. Together these studies identify a unique role for TSP1 in mediating cellular responses to injury during repair: modulation of this pathway represents a novel therapeutic opportunity for treatment of chronic wounds.
Our lab has made the seminal discovery that TSP1 as a major regulator of activation of the pleiotrophic cytokine, TGF-beta. TGF-beta is a key factor that drives the development of fibrotic organ failure, immune regulation, and epithelial cell growth control. TSP1 is a key player in regulating the inappropriately high levels of TGF-beta activity in diabetes and hypertension and in vivo studies suggest that a peptide antagonist of TSP1-dependent TGF-beta activation can attenuate diabetic cardiomyopathy and nephropathy. Ongoing studies are evaluating the utility of these peptides as therapeutics for the treatment of diabetic complications. TSP1 also drives mesenchymal stem cell differentiation into myofibroblasts and inhibits osteogenesis through its action on TGF-beta activity. Corrosion products from metal ions stimulate this TSP1-TGF-beta axis, suggesting that TSP1 can modify host responses to implant materials. Both TSP1 and TGF-beta have been implicated in in-stent restenosis. Our lab has identified a novel molecular mechanism by which metal corrosion materials from endovascular stents drives the cellular processes involved in in-stent restenosis. Proposed studies are aimed at developing new stents which release peptides that inhibit the TSP1-TGF-beta pathway to limit in-stent restenosis.
Our lab is also investigating how fibroblast subsets differentially respond to injury by limiting TGF-beta activation. Using a lung model of fibrosis, we identified that fibroblast expression of Thy-1 limits TGF-beta activation and myofibroblast induction through differential regulation of the latent TGF-beta binding protein 4. We are developing fibroblast-targeted gene therapy approaches to drive expression of Thy-1 in activated lung fibroblasts with the goal of attenuating TGF-beta mediated myofibroblast differentiation and interstitial fibrosis for treatment of idiopathic pulmonary fibrosis.
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