Mechanism of serum amyloid A protein synthesis

在慢性炎症状态下，血清淀粉样蛋白A （SAA）的合成持续高于正常背景水平，且持续时间较长。SAA水平升高与多种疾病的发病机制有关，包括反应性淀粉样变性、关节炎和动脉粥样硬化。SAA水平升高也与阿尔茨海默病有关。

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.