Cloaking Key MMP-9 Substrates to Probe the role of Their Cleavage in Plaque Ruptu

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DESCRIPTION (provided by applicant): Matrix metalloproteinase (MMP)-9 is implicated in plaque rupture that is responsible for the majority of clinical manifestations of cardiovascular disease. However, it is still unclear what key substrates this pleiotropic enzyme cleaves to control the disease process. Using a unique mouse model which reproduces many features of human atherosclerotic plaque rupture, we propose to develop potential therapeutically applicable "cloaking devices" to prevent cleavage of two proteins in pathways that we've shown to be disrupted by MMP-9: tissue factor pathway inhibitor (TFPI) in the coagulation cascade and integrin ¿2 involved in the resolution of inflammation. Rather than binding and inhibiting the enzyme, agents that specifically bind the cleavage site of TFPI and integrin ¿2 will be identified from combinatorial libraries of peptide-like peptoids that have been shown to be a rich source of protein-binding agents. Effective inhibition of MMP-9-mediated proteolysis of TFPI and integrin ¿2 will be established in cell-based systems, and the affinity of peptoid binding and inhibition enhanced if necessary. The ability of the peptoids to prevent features of plaque rupture will then be tested, and will help determine the biological function of substrate proteolysis in disease progression. Exploration of the capacity of peptoids to mediate substrate-selective limitation of proteolysis also has the potential to provide new interventional strategies for cardiovascular disease. PUBLIC HEALTH RELEVANCE: Matrix metalloproteinase (MMP)-9 is implicated in plaque rupture that is responsible for the majority of clinical manifestations of cardiovascular disease, but it is still unclear what key substrates this pleiotropic enzyme cleaves to control the disease process. The goal of this proposal is to develop and test potential therapeutically applicable "cloaking devices" to prevent cleavage of two key proteins involved in the coagulation and inflammatory pathways that we've shown to be disrupted by MMP-9 proteolysis. The proposed studies will determine the biological function of specific substrate proteolysis for disease progression, and may establish a new approach for selective limitation of proteolysis as a potential interventional strategy for cardiovascular disease.