This research continues our studies on the structure of the major histocompatibility complex in the rat with emphasis on biochemical and molecular approaches: First, the immunogenetic definition of the RT1.G (Qa/T1a-like) locus will be completed. Second, the biochemical structure of the class I heavy chains carrying private antigenic specificities will be studied using peptide mapping by HPLC. The following comparisons will be made using monoclonal antibodies and specific alloantisera: Aa to Ad and Af (serologically related) and to Au, An and Al (serologically unrelated); Au, Eu and Cu, and Al, Ga and Cl. The carbohydrate structure of the antigen heavy chains and the polymorphism of the rat B2-microglobulin molecule will also be examined. Third, the three different types of class I loci (A, E, and G) will be analyzed at the molecular level. cDNA libraries will be constructed from the WF (AuEu) and R21 (AlEu) strains, and genes representative of the A and E loci will be sequenced. A genomic library will be constructed from the R21 strain, and the class I loci will be mapped using overlapping cosmids. The RT1.G locus will be studied by first defining the parental strains and the recombinants by RFLP mapping. Then, these animals and a variety of other strains carrying the alleles of G will be analyzed by hybridization with mouse Qa and T1a probes. The R21 genomic library will be probed to search for the G genes. Finally, the tissue expression of G will be determined, and the cDNA for G will be cloned. Fourth, several other MHC loci will be identified at the DNA level using mouse probes and the appropriate recombinant and congenic strains. Fifth, the control of the cellular expression of class I antigens in vivo by trans and cis- regulatory elements will be defined, and the biochemical and molecular mechanisms underlying these effects will be explored. The rat is the major experimental animal for studies in physiology and pharmacology, it is extensively used in transplantation, reproductive immunology, immunogenetics and cancer research. Thus, its detailed genetic definition is crucial for work in these fields. It is also important to study in detail the structure of the MHC in several species so that the generality of the genetic factors controlling host defense mechanisms may be explored and so that the comparative genetics and the evolution of the MHC may be delineated.
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