The goa/ of this project is to test the hypothesis that MMP-9 leads to proteolytic cleavage of key regulators of coagulation and inflammation that promote plaque rupture and to compare proteolytic targets in ruptured human and mouse lesions.
Examination of atherosclerotic lesions from humans and animal models has established a central role for macrophages in disease progression and plaque disruption. Despite these observations, it is still unclear what changes within the lesions result in plaque rupture that is responsible for the majority of clinical manifestations of atherosclerosis. With funding from this RO1, we have shown for the first time that over-expression of the protease MMP-9 in macrophages within mouse lesions is sufficient to induce many features of plaque rupture. This proposal will build upon the identification of two pathways disrupted by MMP-9 cleavage of specific substrates: the coagulation cascade and resolution of inflammation. Potential therapeutically applicable cloaking devices will be developed to prevent cleavage of the identified substrates, and their impact on the cellular pathway and plaque disruption will be examined. Finally, we will use targeted proteomics approaches to further probe proteolytic substrates within both mouse and human lesions with plaque rupture.
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