Abnormal synthesis of serum amyloid A (SAA) protein, especially at nonhepatic tissues, during chronic inflammatory conditions is implicated in the pathogenesis of secondary amyloidosis, rheumatoid arthritis, juvenile arthritis, and atherosclerosis. The long term goal of this project is to develop highly specific therapeutic measures capable of curing the above mentioned diseases. It is hypothesized that pro-inflammatory cytokines, released during chronic inflammation, trigger a cascade of intracellular molecular events leading to the activation of some specific transcription factors which induce SAA transcription. A novel family of transcription factors, SAF, has been identified which plays a critical role in regulating inducible expression of SAA. Elucidation of the intrinsic properties of SAF including its activation and mode of action will allow development of inhibitory compounds that are capable of blocking its activation. This proposal focuses on controlling the inducible synthesis of SAA by affecting the activation of SAF. Our objectives are: 1. Identification of signalling mechanism(s) that activates SAF during inflammatory conditions. 2. Analysis of modular domains of SAF family members. 3. Effect of SAF over-expression on the target gene expression. 4. Understanding the regulation of SAF gene. 5. Identify the residues that contribute to high-affinity binding, and to define positions where sequence variations are tolerated, by screening large libraries of random 15-mer peptides in a phage display assay. 6. Test of peptides selected for anti-SAF activity. Further, results obtained from this study will improve our understaning of the basic mechanisms of cellular response to inflammation and lead toward the design of treatments to reduce the harmful effects of chronic inflammation and increase the rate of recovery from tissue damage.
| Ray, Alpana; Dhar, Srijita; Shakya, Arvind et al. (2009) SAF-3, a novel splice variant of the SAF-1/MAZ/Pur-1 family, is expressed during inflammation. FEBS J 276:4276-86 |
| Ray, Bimal K; Murphy, Ryan; Ray, Papiya et al. (2002) SAF-2, a splice variant of SAF-1, acts as a negative regulator of transcription. J Biol Chem 277:46822-30 |
