MECHANISM OF SERUM AMYLOID A PROTEIN SYNTHESIS

慢性炎症期间血清淀粉样蛋白A （SAA）的异常合成，特别是在非肝组织，与继发性淀粉样变性、类风湿关节炎、幼年关节炎和动脉粥样硬化的发病机制有关。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。据推测，在慢性炎症过程中释放的促炎细胞因子触发了一系列细胞内分子事件，导致一些特异性转录因子的激活，从而诱导SAA转录。一个新的转录因子家族，SAF，已经被确定在调节SAA的诱导表达中起关键作用。阐明SAF的内在特性，包括其活化和作用方式，将有助于开发能够阻断其活化的抑制化合物。本研究的重点是通过影响SAF的活化来控制SAA的诱导合成。我们的目标是：1；识别炎症条件下激活SAF的信号机制。2. SAF族成员的模域分析。3. SAF过表达对靶基因表达的影响。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的大型15-mer肽库，确定有助于高亲和力结合的残基，并确定序列变化可耐受的位置。6. 选择抗saf活性的肽的测试。此外，从本研究中获得的结果将提高我们对细胞对炎症反应的基本机制的理解，并指导设计治疗方法，以减少慢性炎症的有害影响，提高组织损伤的恢复速度。

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.