Mechanism of serum amyloid A protein synthesis

在慢性炎症状态下，持续高于正常本底水平的血清淀粉样蛋白A(SAA)会在较长时间内合成。SAA水平升高与多种疾病的发病有关，包括反应性淀粉样变性、关节炎和动脉粥样硬化。SAA水平升高也与阿尔采默氏病有关。 该项目的长期目标是开发高度特异的治疗措施来控制这些 疾病。由于SAA的表达在这些疾病的发病中起着关键作用，因此对SAA表达的机制进行了研究，从而确定了一种被称为SAA激活因子(SAP)的调节转录因子。据推测，通过控制SAF的活性，有可能控制和治愈一些由慢性炎症引起的疾病。 这种可能性的成功取决于对SAP结构和功能特性的广泛了解。因此，这一建议侧重于通过靶向激活SAP和直接抑制SAA mRNA的积累来控制SAA基因的表达。为了实现这一目标，计划实现以下目标：1.通过siRNA介导的SAA mRNA降解来抑制SAA的生物合成。2.检测泛素-蛋白酶体介导的蛋白加工途径的抑制剂是否会减少SAA的生物合成，并控制与慢性炎症相关的严重程度。3.SAP剪接变异体的功能特性。4.体内靶向表达SAF-1，评价SAF-1的病理生理效应。5.靶向阻断SAP基因对小鼠模型的影响。这些研究的结果将提高对细胞对炎症和 帮助制定治疗方案，以控制慢性炎症的有害影响。

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.