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- Title
- Inhibition of matrix metalloproteinase-9 reduces clinical severity in a murine model of Multiple Sclerosis.
- Creator
- Onwuha-Ekpete, Lillian C., Tokmina-Roszyk, Dorota, Fields, Gregg B., Graduate College
- Abstract/Description
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Matrix metalloproteinases MMPs are a family of proteolytic enzymes that mediate the degradation of various components of the extracellular matrix. Their functions are essential for normal physiological processes such as wound healing, but their dysregulation is associated with various pathologies including autoimmune diseases such as Multiple Sclerosis MS. Experimental Autoimmune Encephalomyelitis EAE is a well-established murine model of MS that is mediated by CD4 T-cells. These cells...
Show moreMatrix metalloproteinases MMPs are a family of proteolytic enzymes that mediate the degradation of various components of the extracellular matrix. Their functions are essential for normal physiological processes such as wound healing, but their dysregulation is associated with various pathologies including autoimmune diseases such as Multiple Sclerosis MS. Experimental Autoimmune Encephalomyelitis EAE is a well-established murine model of MS that is mediated by CD4 T-cells. These cells penetrate the blood-brain-barrier BBB, recruit other immune cells, initiate destruction of the myelin sheath, and cause axonal loss. MMP-9 is a hallmark enzyme in progression of MS that is required for penetration of the BBB and generation of autoantigens in EAE. In addition, recent studies have demonstrated that MMP-9 contributes to normal intracellular function of various cell types including antigen activated T-cells; however, the intracellular role of MMP-9 in immune cell activation during EAE pathogenesis is not known. In this study, we used a highly selective MMP-9 triple-helical peptide inhibitor THPI that is a phosphinate transition state analog to examine antigen specific T-cell responses. We found that selective inhibition of MMP-9 can mitigate pathogenic T-cell activity and cellular trafficking as well as the clinical severity of EAE, suggesting that selective MMP-9 inhibition in MS can be a potent therapeutic option.
Show less - Date Issued
- 2015
- PURL
- http://purl.flvc.org/fau/fd/FA00005904
- Format
- Document (PDF)
- Title
- Matrix metalloproteinase-9 (MMP-9) in vivo substrates in left ventricle remodeling process.
- Creator
- Tokmina-Roszyk, Dorota, Iyer, R.P., Lindsey, M.L., Graduate College, Fields, Gregg B.
- Abstract/Description
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Matrix metalloproteinase-9 MMP-9 is involved in the early stages of wound healing, including the inflammatory reaction that follows myocardial infarction and neovascularization. However, its overexpression in the infarct zone leads to deleterious effects. Understanding MMP-9 function and modulation of its activity provides an opportunity to prevent excessive remodeling of the left ventricle. To assess the role of MMP-9 in remodeling process we employed a broad search of in vivo substrates....
Show moreMatrix metalloproteinase-9 MMP-9 is involved in the early stages of wound healing, including the inflammatory reaction that follows myocardial infarction and neovascularization. However, its overexpression in the infarct zone leads to deleterious effects. Understanding MMP-9 function and modulation of its activity provides an opportunity to prevent excessive remodeling of the left ventricle. To assess the role of MMP-9 in remodeling process we employed a broad search of in vivo substrates. Based on comparative analysis of MMP-9 null and wild type mice, several peptides mimicking putative substrates were synthesized. The cleavage sites in the substrates were identified using high performance liquid chromatography and mass spectrometry. Peptide mapping studies revealed MMP-9 cleavage sites in several proteins, potential biomarkers of excessive remodeling. Specifically, osteopontin, thrombospondin and C-terminal telopeptide regions of type I collagen were susceptible to proteolysis by MMP-9. The best target for MMP-9 was fibronectin, which has multiple cleavage sites in its sequence. In addition to in vivo substrate screening, a selective triple-helical peptide inhibitor MMP- 9i has been designed, synthesized, and utilized as an MMP-9 probe. The sequence of inhibitor was derived from the known MMP-9 substrate type V collagen. In the MMP-9i construct, the G~V scissile bond has been replaced with phosphinate moiety that mimics the transition state of hydrolysis but cannot be cleaved. MMP-9i's effect on MMP-9 activity in serum was tested in a mouse model. The administration of MMP-9i resulted in 30 loss of MMP-9 activity suggesting that MMP-9i can be utilized to regulate activity of MMP-9 in vivo.
Show less - Date Issued
- 2015
- PURL
- http://purl.flvc.org/fau/fd/FA00005917
- Format
- Document (PDF)