The long term career objectives are to establish a research program that makes significant contributions to the overall understanding of the molecular and cellular mechanisms involved in the regulation of isotype switching to IgA, the maturation of mIgA expressing cells to IgA secreting cells, and the generation of an IgA memory response. The immediate career objectives are to determine the molecular basis for the differential regulation of membrane and secreted forms of alpha and mu mRNAs, the role of mlgA expression in athe generation of IgA secreting cells, and athe mechanism for the increased stability of alpha mRNA that is associated with isotype switching to IgA in murine B cells.
The specific aims of the research aspect of this proposal are to determine the properties of the alpha gene responsible for the predominance of the secreted form of alpha mRNA, the basis for the differential regulation of 3' terminus usage by alpha and mu mRNA, and athe relevance of IgA expression to the generation of igA secreting cells. To accomplish these aims, specific sequences in alpha will be altered and the effect of those alterations ont he steady state levels of the membrane and secreted forms of alpha mRNA will be measured. In addition, trans-acting factors that bind to alpha and /or mu will be identified by gel mobility shift assays. Gene targeting by homologous recombination will be used to create an insertional mutation in the membrane exon of alpha in a mlgM+, mlgA- lymphoma that spontaneously switches to IgA expression/secretion, and the effect of the mutation on the ability of the cells to mature to IgA secretion will be measured. Finally, gene targeting will be used to generate animals that do not express mlgA.
| Guilliano, M J; Foxx-Orenstein, A E; Lebman, D A (2001) The microenvironment of human Peyer's patches inhibits the increase in CD38 expression associated with the germinal center reaction. J Immunol 166:2179-85 |
