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Characterizing inhibitors of the mutagenic retrotransposon LINE I endonuclease

In view of the paucity of knowledge about differences in inflammatory response between Gram-negative and Gram-positive organisms during COPD, the focus of the present proposal is to determine the effect of microbial toxins from both Gram-negative and Gram-positive organisms in presence of cigarette smoke extract (CSE) using human monocyte derived macrophages (MDMs) and murine airway epithelial (LA-4) cells. The NF-_B comprises a family of transcription factors that are involved in regulating a large number of genes related to immune function, inflammation, apoptosis and cell proliferation. Many chronic disease states have been associated with aberrant activation of NF-_B and several therapeutic strategies target NF-_B activation have been considered for the treatment of inflammation and cancer. Histone deacetylases (HDACs) play a key role in the activation of transcription factors like NF-_B. Among others, HDAC1, HDAC2, and HDAC3 interact directly with NF-_B; however, their precise role remains controversial. Reports suggest acetylation of NF- _B/p65 either suppresses or activates its transcription depending on the biological context of the cell. Studies are designed to understand the differences in immune responses between microbial toxins from Gram- negative and Gram-positive organisms in human MDMs and airway epithelial cells exposed to CSE. We propose to determine the effect of lipopolysaccharide (LPS, from Gram-negative Peudomonas aeruginosa) and lipoteichoic acid (LTA) or peptidoglycan (PG) from Gram-positive bacteria on the co-activators or co-repressors including histone acetyltransferases (HAT) and HDACs, transcription factors and cytokine/chemokine levels in the presence and absence of CSE. PI�s earlier report has shown that benzyl isothiocyanate (BITC), a dietary agent leads to a significant decrease in the expression and activity of HDAC1 and HDAC3 in pancreatic cancer cells. Supportive data from other studies on BITC include demonstration of chemopreventive and anti- inflammatory effects in murine macrophages in response to LPS challenge. The anti-inflammatory properties of BITC and the associated molecular mechanisms in response to challenge with other microbial toxins or during cigarette smoke exposure have however not been explored yet.