Mechanism of serum amyloid A protein synthesis

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During chronic inflammatory condition, persistently higher than normal background level of serum amyloid A (SAA) is synthesized for a prolonged period of time. Elevated level of SAA is implicated in the pathogenesis of several diseases, including reactive amyloidosis, arthritis and atherosclerosis. Elevated level of SAA is also linked to Alzeimer's disease. Long term goal of this project is to develop highly specific therapeutic measures to control these diseases. Since SAA expression plays a critical role in the onset of these ailments, studies on the mechanism of SAA expression were undertaken, which led to the identification of a regulatory transcription factor called SAA activating factor (SAP). It is hypothesized that by controlling SAF activity, it is possible to control and cure some of these ailments resulting from chronic inflammation. Success of this possibility depends on the extensive knowledge about the structural and functional properties of SAP. This proposal, thus, focuses on controlling SAA gene expression by targeting activation of SAP and by direct inhibition of SAA mRNA accumulation. Towards this goal, the following objectives are planned to pursue: 1. Suppression of SAA biosynthesis by siRNA-mediated degradation of SAA mRNA. 2. Test if inhibitors of ubiquitin-proteosome mediated protein processing pathway would reduce SAA biosynthesis and control the severity associated with chronic inflammation. 3. Functional properties; of SAP splice variants. 4. Targeted in vivo expression of SAF-1 to evaluate the pathophysiological effect. 5. Effect of targeted disruption of SAP gene in mouse model. Results of these studies will improve understanding of the basic mechanisms of cellular response to inflammation and help in the development of a therapeutic regimen to control harmful effects of chronic inflammation.