The murine H-2 major histocompatibility complex or MHC controls a diverse set of products and traits whose definition is important to the understanding of fundamental genetic and immunologic mechanisms, as well as to clinically relevant research in transplantation and disease resistance. In the latter context, H-2 is an important experimental model for the human MHC, the HLA gene complex, because of their remarkable genetic and functional homology. The long-term objective of this research is to resolve, by genetic, biochemical and functional approaches, the multiple genes of the H-2 complex, in order to advance our understanding of the organization, evolution and regulation of the MHC genes. This research will focus particularly upon the genes of the internal I and S regions of the H-2 complex, whose products mediate macrophage-T lymphocyte-B lymphocyte regulatory interactions, and reactions of the complement pathways, respectively. Two general approaches are to be taken: 1) Efforts will be made to detect and characterize new mutations and recombinations, to improve H-2 genetic fine structure mapping and to provide new and useful stocks for further functional and biochemical studies. Progeny from mutagen-treated parents will be screened by mixed leucocyte reactions and with monoclonal antibodies to cellular alloantigens. Variants will be characterized serologically, biochemically and functionally, with emphasis on improved definition of the I-A, I-B, I-J, S and D regions. 2) The structure, synthesis and processing of the S region C4 and Slp protein will be investigated, to better define the genetic information that specifies their structures and the genetic and hormonal regulatory mechanisms that control their expression. Peptide mapping and amino acid sequence determinations will be done. The roles of proteolytic cleavage and of glycosylation in processing of intracellular precursors will be examined. Tissue sites of synthesis will be determined. C4 and Slp mRNA will be examined to probe regulatory mechanisms. Non-H-2 genes regulating Slp expression will be further defined.
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