A mammalian multigene family, the serum amyloid A (SAA) gene family, is differentially regulated during inflammation. Normal expression of SAA is extremely low; however, in response to acute inflammation, the acute-phase SAAs are dramatically induced by up to 1,000 fold. SAA is synthesized and secreted primarily by the liver and associates with the third fraction of high density lipoprotein (HDL3) on which it replaces apolipoprotein A1 as the predominant apolipoprotein. While the magnitude of their induction suggests a critical short-term survival function, prolonged elevation of plasma SAA protein, however, will lead to secondary amyloidosis, an incurable disease. Studies have shown that SAA expression is regulated by the circulating inflammatory cytokine interleukin-1 (IL-1) and that transcription factors C/EBP and NFkB are centrally involved in their transcription activation. In addition to trans-activators, SAA1 is also regulated negatively by transcription repressor YY1 and the level of SAA1 expression is dependent on the relative concentrations of activators and repressor. As with its regulation by activators and repressor in response to cytokine stimulation, its liver-tissue specificity is also regulated by positive and negative regulators. The principal investigator's identification of a binding factor that demonstrates tissue-specific distribution and may function to repress SAA1 expression in nonliver tissues is particularly exciting. The diverse features of this differential expression, together with its regulation by a tissue-specific repressor, make the SAA gene family an informative model to examine the molecular mechanisms underlying the complexity of gene control. Dr. Liao's overall objective is to understand the molecular mechanisms involved in the transcriptional regulation of SAA genes with respect to cytokine stimulation as well as tissue specificity and begin to understand the function and regulation of these transcriptional regulators. Furthermore, he aims to understand the pathogenesis of secondary amyloidosis caused by persistent over-expression of SAA. Such studies have the potential to generate new insights into the molecular evolution of regulatory mechanisms elicited by inflammatory processes and ways to modulate them.
The specific aims are: 1. to examine the molecular basis of SAA1 and SAA3 gene regulation; 2. to clone cDNAs of the tissue specific repressor (TSR) and the SAA enhancer binding factor (SEF-1) and study their functions in SAA and liver gene regulation; 3. to study the pathogenesis of secondary amyloidosis using a transgenic animal model.
