GENETIC REGULATION OF THE HEPATIC ACUTE PHASE RESPONSE

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The molecular machinery for control of gene expression is modified during evolution, resulting in the appearance of species-specific alterations in gene regulatory patterns. Analysis of these modifications provides novel insights into the nature and mechanisms of action of molecular elements that determine gene activity and that are primary targets for the evolutionary process. To address this issue, we have developed the acute phase protein genes of mice as a model. These genes, which encode a number of plasma proteins secreted by the liver are coordinately induced during an acute inflammation; induction is mediated by the combined action of several hormones, including interleukin-1, interleukin-6, and glucocorticoids. Importantly, the structure and expression of the acute phase genes exhibit extensive variation among mouse species. In addition, while the overall spectrum of hepatic genes responding to an acute phase is conserved among mammalian species, including mice, the exact mechanisms by which these genes respond are not. In this renewal application, we propose to continue the molecular genetic analysis of interspecies variations in acute phase protein gene regulation, focusing on the two multi-gene system of alpha(1)-acid glycoprotein (AGP), and alpha(1)-antitrypsin (AT) that evolved in the three phylogenetically representative Mus species, M domesticus, M caroli, and M saxicola. Specific questions of primary interest include: How have the hormonal regulatory elements within the AGP gene cluster been rearranged, and what new response elements have evolved in the Mus species in comparison to the single gene copy system of rat? What is the nature of the regulatory elements responsible for unusual renal expression of the AT gene in M caroli and M saxicola, and what controls the expression of the different genes in the liver during normal physiologic and stress states? Our fundamental goal is to define and characterize the cis- and trans-acting factors responsible for the evolutionarily-derived alterations in gene expression phenotypes. Our efforts will provide new information regarding the molecular machinery that controls the mammalian acute phase response and its evolution; such information will add significantly to our general understanding of gene transcription and its regulation in the mammalian liver.