Mammalian livers respond to different kinds of tissue injury such as infarction, tumors, infection or surgery, by a profound but reversible change in the expression of several proteins. Most prominent is the coordinate increase in the production of a subset of essential plasma proteins, the acute phase reactants. To dissect this complex heaptic response, we propose to study regulatory mechanisms acting in mouse liver cells during an acute inflammation by applying genetic, cellular and molecular techniques. In order to examine the structure and expression of specific genes in liver cells at the molecular level, we shall isolate cDNA plasmids complementary to the mRNAs for the major acute phase proteins. Encouraged by recent results, we shall continue to screen inbred strains and wild derived subspecies of Mus musculus for genetic polymorphism in the structure and regulation of the acute phase proteins. Major attention will be given to regulatory variants which affect either the basal level or the magnitude of induction of a single or a subgroup of acute phase reactants. The existence of structural variants will allow mapping the corresponding structural genes. In conjunction, we shall assign linkage to regulatory loci for which allelic forms have been recognized. The mode of action (cis vs. trans) of regulatory variants will be determined in progeny of appropriate crosses. The basis for variation in trans-acting genetic loci will be determined in primary cultures of adult hepatocytes; such analysis may enable identification of diffusable factors (hormones, etc.) that regulate the hepatic acute phase response. As already suggested by current progress, this program will provide new information about the acute phase protein genes and their regulation. Furthermore, by employing a genetic approach, we might be able to identify and study regulatory mechanisms which are not amenable to analysis by cell biological methods.