The pathophysiology associated with numerous chronic non-infectious inflammatory diseases, cardiovascular diseases, diabetes and possibly certain cancers is due in part to a dysregulated innate immune response. In vivo, the cytokine, Tumor necrosis factor-alpha (TNFα) is required for innate immune response activation. A key transcriptional regulators of TNFα induced genes is the NF-kappaB/c-rel family of transcription factors. We have determined that the interleukin-1 receptor associated kinase [IRAK-1, also known as the mouse pelle-like kinase (mPLK)] functions in a TNFα dependent pathway that leads to activation of NF-κB dependent gene expression. We have identified an IRAK-1 substrate termed SIMPL (signaler that interacts with mPLK) which is a nuclear protein that synergizes with p65 to promote endogenous NF-κB dependent gene expression. How TNFα regulates IRAK-1 catalytic activity and the functional significance of IRAK-1 induced modulation of SIMPL activity are unknown. We have generated a SIMPL knock-out mouse and are in the process of defining its phenotype in the context of hematopoiesis and non-infectious chronic inflammatory diseases. Proteomic and genomic based approaches are being used to identify controlled cellular events, to determine how IRAK-1 activity is regulated; to determine the role SIMPL plays in the regulation of p65 dependent transcription and to determine how SIMPL activity is regulated. A second research focus in the lab is on the role the inflammatory response plays in the development of ovarian cancer. We are using a syngenic mouse model of ovarian cancer to explore whether the expression of TNFα dependent signaling pathway components alters the development of ovarian epithelial cell cancers.