Atherosclerosis and thrombosis are the two pathological processes with the most impact on ischemic stroke and cardiovascular disease (CVD). Therefore, pharmaceutical therapies that target the mechanisms causing atherosclerosis and thrombosis are important for the treatment and prevention of stroke and cardiovascular disease. Thrombin is a serine protease that is the ultimate enzyme in the coagulation cascade. Additionally, thrombin has proinflammatory functions that contribute to the development of atherosclerosis. Serine protease inhibitors (serpins) are a family of proteins with high structural homology. The sequence or structural domain unique to each serpin determines its specificity for a protease and the cofactors that control its inhibition. Many endogenous serpins are known to inhibit thrombin and other proteases that contribute to atherosclerosis and thrombosis. The goal of this project is to engineer a chimeric serpin comprising sequences and structures from a number of serpin family members that will have both anti-atherogenic and anti-thrombotic properties without compromising hemostasis. I will use the prototypical serpin alphal-protease inhibitor as the scaffold for my chimera. I will then substitute sequences and structures from heparin cofactor II and antithrombin to alter protease specificity. The chimera activity will be monitored by a number of in vitro assays examining both specific protease activity and thrombin generation in a cell-based model of heomstasis. Successful development of this chimeric serpin will result in a protein that can be tested in ischemic stroke and cardiovascular disease animal models in this laboratory and ultimately lead to a novel treatment for stroke and CVD that protects against both thrombosis and atherosclerosis.
| Rau, Jill C; Mitchell, Jennifer W; Fortenberry, Yolanda M et al. (2011) Heparin cofactor II: discovery, properties, and role in controlling vascular homeostasis. Semin Thromb Hemost 37:339-48 |
| Rau, Jill C; Deans, Carolyn; Hoffman, Maureane R et al. (2009) Heparin cofactor II in atherosclerotic lesions from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study. Exp Mol Pathol 87:178-83 |
