Onwuha-Ekpete, Lillian C.

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 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.

We attempted to understand the molecular regulators that impact inflammation using a rat model of human sensation-seeking/risk-taking trait for drug and stress vulnerability, based on their exploratory behavior displaying high rates (HRs) or low rates of locomotor reactivity (LRs) to environmental stress. We found that HRs have a pro-inflammatory phenotype as indicated by increased protein expression of the inflammatory cytokine TNF-(Sa(B. Furthermore, we found that HRs have a lower gene expression of the glucocorticoid receptor and histone deacetylase 2 which are known to play an immunosuppressive role. Autophagy (macroautophagy) is a homeostatic process needed for cell maintenance, growth and proliferation and known to assist in tumor survival. FYVE and coiled-coil domain containing 1 (FYCO1) is a novel protein implicated to assist in the plus-end directed trafficking and fusion of autophagosomes. In these studies, we show that FYCO1 gene expression among human breast cell lines of varying degrees of malignancy.