This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.In lupus, both drug-induced and idiopathic, several methylation sensitive genes are overexpressed including CD11a, CD70 and perforin. Indeed, it has been shown and confirmed that this overexpression is due to promoter sequence hypomethylation. Further, T cells treated with DNA methylation inhibitors become autoreactive in vitro, and upon adoptive transfer, produce autoimmunity in animal models. DNA methylation is mediated by a family of enzymes namely, the DNA methyltransferases. The expression of DNA methyltransferases in T cells is at least in part regulated by signaling through the MEK/ERK pathway. Indeed, T cells treated with MEK/ERK pathway signaling inhibitors overexpress methylation sensitive genes similar to T cells from lupus patients. Further, T cells treated with MEK/ERK pathway inhibitors become autoreactive and produce autoimmunity in vivo. We propose to further study and characterize the effect of inhibiting MEK/ERK pathway signaling on DNA methylation in T cells. We also propose to investigate the contribution of decreased T cell MEK/ERK pathway signaling and the overexpression of the methylation sensitive genes to autoimmunity using transgenic murine models. Furthermore, using genetic association approaches, we propose to study the genetic polymorphisms of the methylation sensitive genes CD70 and perforin, both shown to be overexpressed in T cells from lupus patients. These two genes are chosen because genetic linkage has been established and confirmed in lupus families on the chromosomal regions where the two genes reside.
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