The regulation of appropriate antigen-specific immune responses to pathogen is crucial for human health. Inappropriate immune responses underlie many human diseases including rheumatoid arthritis, diabetes, lupus and heart disease. Understanding the molecular mechanisms involved in regulation of the immune response is one road to discovering new therapies for these diseases. Ikaros is a nuclear transcriptional regulator that is expressed almost exclusively in cells of the hematopoietic lineage from the level of the hematopoietic stem cell. It is clear, through analyses of genetically engineered Ikaros null mice, that Ikaros activity is required for normal immune system development. Defects in Ikaros null mice include a total lack of B and natural killer cells, selective lack of some lineages of dendritic and ?dT cells and defects in a?T cell development. However, the role of Ikaros in the function of mature immune system cells during the course of an in vivo immune response is still unknown. This is due to the complex phenotype of Ikaros null mice that display, in addition to the multitude of defects in development of hematopoietic and lymphoid lineage cells, a total lack of development of lymph nodes. This has been a critical barrier in the field in understanding Ikaros'function. In order to overcome these obstacles, we propose to develop a system by which Ikaros'function can be deleted selectively in specific immune cell subsets in the mouse. We will do this by creating a conditional Ikaros null allele through the use of Cre-lox technology. This will be done with the assistance of the Mouse Biology Program (MBP) at University of California, Davis. Once generated, this mouse model system will be extremely valuable to study the role of Ikaros in multiple blood cell lineages, through the use of different Cre-transgenic mice. We will prioritize studies focused on the role of Ikaros in mature T and B lymphocytes during the course of an immune response as well as in investigation of how lack of Ikaros within these lineages may result in immune dysfunction leading to disease. Taken together, these studies will provide valuable insight into the in vivo function of Ikaros in the immune response.
Inappropriate immune responses can underlie many human diseases including rheumatoid arthritis, diabetes, lupus and heart disease. Understanding the molecular mechanisms involved in regulation of the immune response is one road to discovering new therapies for these diseases. In the studies proposed here, we will generate a new mouse model system with which to investigate these mechanisms.
