The long-term objective of this research project is to understand the genetic, molecular, and cellular factors that influence the expression of the antibody repertoire. A detailed study will be made of the genes coding for mouse immunoglobulin heavy chain variable regions (Igh-V genes or Vh genes). Studies will focus on the influence of chromosomal organization on Vh gene expression, the differential expression of Vh genes in B cell subpopulations, and the temporal sequence of expression of Vh genes in early development. The planned experiments are designed to test the hypothesis that Igh-V gene families, sets of genetically clustered and highly homologous Vh genes, are expressed at different frequencies within cell subpopulations and during ontogeny. Specifically, the proposed experiments will 1) complete the characterization and genetic mapping of Vh gene families, 2) refine the map of the Igh-V locus and compare the orientation of the two most Dh proximal Vh families in different Igh haplotypes, 3) develop in situ mRNA hybridization methodology to quantitate the frequency of Vh family usage in B cell subsets and pre-B cells, 4) quantitate Vh family usage during ontogeny, and 5) undertake a genetic analysis of Vh gene family expression using Igh-congenic, Igh-Recombinant, and Recombinant Inbred mouse strains. In addition, Vh family expression will be studied in autoimmune strains in an attempt to gain insight into the etiology of immune disease.
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