MECHANISM OF SERUM AMYLOID A PROTEIN SYNTHESIS

血清淀粉样蛋白A（SAA）蛋白的异常合成，特别是在非肝组织，在慢性炎症条件下，涉及继发性淀粉样变性，类风湿性关节炎，幼年型关节炎和动脉粥样硬化的发病机制。该项目的长期目标是开发能够治愈上述疾病的高度特异性治疗措施。 假设在慢性炎症期间释放的促炎细胞因子触发细胞内分子事件的级联反应，导致诱导SAA转录的一些特异性转录因子的激活。 一个新的转录因子家族，SAF，已被确定在调节SAA的诱导表达中起着关键作用。 阐明SAF的内在性质，包括其活化和作用模式，将允许开发能够阻断其活化的抑制性化合物。该建议的重点是通过影响SAF的活化来控制SAA的诱导合成。 我们的目标是：1.识别在炎性病症期间激活SAF的信号传导机制。 2. SAF家族成员的模块结构域分析。 3. SAF过表达对目的基因表达的影响。 4.了解SAF基因的调控。 5.通过在噬菌体展示试验中筛选随机15聚体肽的大型文库，鉴定有助于高亲和力结合的残基，并确定序列变异被容忍的位置。 6.针对抗SAF活性选择的肽的测试。此外，从这项研究中获得的结果将提高我们对炎症细胞反应的基本机制的理解，并导致治疗设计，以减少慢性炎症的有害影响，并提高组织损伤的恢复率。

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.