Loss of appropriate inflammatory regulation contributes to numerous chronic conditions (i.e. auto-inflammatory disorders, Alzheimer's, heart disease), the development of cancer, and when severely acute, can result in multi-organ failure and death. Higher primates code for a pyrin-only protein (POP2) which can modulate the inflammatory response, and has been demonstrated to inhibit both pro-inflammatory cytokine gene expression through its blockage of NF-kB, and the maturation of cytokines by interfering with inflammasome assembly. The long-term goals of this laboratory are to elucidate the biological significance of POP2 in the context of inflammatory based diseases and its molecular mechanisms of action, so that this information can be used to design more specific chemotherapeutics for control of inflammatory-mediated diseases. Thus the work proposed here is to establish the mechanisms by which POP2 modulates NF-kB activity and how this relates to altered pro-inflammatory cytokine release from macrophages. We hypothesize that POP2 impairs NF-kB by acting as a competitive inhibitor for activating kinases, which contributes to differential control of inflammatory cytokines. The experiments proposed here utilize mutagenesis strategies and established methods for monitoring gene promoter usage, transcription factor binding and gene expression. Completion of the proposed experiments will give a better understanding for how a primate-specific, endogenous modulator of NF-kB exerts its function for the design of more targeted and effective anti-inflammatory drugs.
Unchecked inflammation is at the route of numerous acquired and infectious diseases as well as cancer. We seek to establish the mechanism of action the endogenous mediator of inflammatory responses, POP2, to aid in the design of more specific and effective anti-inflammatory chemotherapeutics.
Porter, K A; Duffy, E B; Nyland, P et al. (2014) The CLRX.1/NOD24 (NLRP2P) pseudogene codes a functional negative regulator of NF-?B, pyrin-only protein 4. Genes Immun 15:392-403 |