Date of Award

2008

Degree Type

Thesis

Department

Chemistry

First Advisor

Zhou, Aimin

Subject Headings

Nitric-oxide synthase, Cytology, Inflammation -- Immunological aspects, Cellular biology

Abstract

Macrophages and other leukocytes play a vital role during inflammation. IFN-Îđ which is secreted by Th1 cells activates monocyte-macrophages and this activation leads to induction as well as suppression of certain genes expressed during inflammation. This suppression of genes may be potentially vital for resolution of inflammation. Upon IFN-Îđ stimulation, a Gamma-activated inhibitor of translation complex (GAIT) is formed, which binds to 3'-UTR of target mRNAs thereby silencing their translation. VEGF-A and ceruloplasmin are two proteins whose translation is suppressed by this pathway. The GAIT complex proteins have been identified as ribosomal protein L13a, glutamyl-prolyl tRNA synthatase (EPRS), NS-1 associated protein 1 (NSAP-1), and glyceraldehyde-3 phosphate dehydrogenase (GAPDH) (Mazumder et al., 2003 Sampath et al., 2004). The cellular abundance of the proteins involved in GAIT complex formation is in excess of Cp or VEGF mRNA, so we hypothesize that there exists additional mRNAs that are subject to GAIT-mediated translational control. Hence further studies were done to investigate other possible targets of this pathway. A probable list of targets containing putative GAIT-like elements in 3'-UTR were obtained using pattern search, a bioinformatic approach (Ray and Fox, 2007). Among these targets, inducible nitric oxide synthase (iNOS) was found to be of particular interest as nitric oxide which is produced by enzymatic activity of nitric oxide synthases, is central for the function of macrophages and also for early immune responses to invading microorganisms. Apart from iNOS, translational silencing of putative GAIT element bearing mRNAs of ADAM10, GLUT10, LITAF, GABA B receptor and mouse iNOS in their 3'-UTR was also investigated in IFN-Îđ treated monocytic cells which suggests that there might be additional targets of this pathway

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