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Characterization of Matrix Metalloproteinase-8 (MMP-8) Structure and Stability and the Effects of Its Interaction with the Inhibitory Metal Abstraction Peptide NCC Using High-Resolution Solution NMR

Schlemmer, Alana
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Abstract
Matrix metalloproteinases (MMPs) are important enzymes for extracellular matrix degradation. Cleavage of collagen by MMP-8 is an important regulator of tissue remodeling in wound healing and repair, but it also contributes to the exacerbation of several inflammatory diseases and can serve a protective role in early stages of cancer. In addition through its enzymatic activity, MMP-8 directly effects disease progression through up-regulation or down-regulation of key inflammatory mediators and proteins involved in tissue repair, neutrophil migration, and inflammation. As such, MMP-8 has been a therapeutic target for inhibition with the aim to improve patient care and outcomes for several inflammatory diseases, such as periodontitis, asthma, and rheumatoid arthritis. Several MMP-8 inhibitors have been investigated, but often, the mechanisms of inhibition are not fully understood. To better understand MMP-8 inhibition, high-resolution solution nuclear magnetic resonance (NMR) spectroscopy has been used to study protein structure under different conditions and to track perturbations from inhibitor interactions. Knowing the mechanism of inhibitor interaction would allow for the development of more selective and potent MMP-8 inhibitors. The primary objectives of this thesis are to give an overview of the mechanistic action of MMP-8 in the immune response, to understand the structure and behavior of MMP-8 in various conditions using NMR spectroscopy, and to explore interaction of this enzyme with the unique metal abstraction peptide (MAP) inhibitor NCC.
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Date
2016-08-31
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University of Kansas
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Keywords
Chemistry, Inflammation, MMP-8, NCC, NMR
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