Title: THE REGULATION OF BASAL INTERFERON AND ITS ROLE IN NECROPTOSIS Necroptosis is a newly described, clinically significant form of necrotic cell death affecting a broad range of pathologies. Excessive and uncontrolled necroptosis can result in excessive pathogen replication while excessive necroptosis is associated with poor outcomes in ischemia reperfusion injuries and models of sepsis. Studying the regulation of necroptosis becomes critical to provide new targets for therapeutic intervention. In addition, some pathogen effectors are thought to hijack necroptotic signaling to increase their survival thus making mechanism of necroptosis an important area of research. Recently, type 1 interferons including interferon a and b have been shown to induce necroptosis directly. It has long been known that low levels of interferon b are constitutively produced in resting cells (basal interferon). Here we report the novel observation that constitutive interferon beta production is required for LPS induced necroptosis in both mouse and human cells. Ultimately we plan to identify one or more genes that are regulated by the basal interferon for expression and potentiate necroptosis. Additionally, we have identified an evolutionarily divergent mouse strain, MOLF, as defective in basal IFN production. We are therefore uniquely positioned to dissect a novel cross-talk pathway linking autocrine interferon signaling and cell death. Using a combination of biochemical approaches, we will investigate the mechanism of activation of necroptosis by basal IFN. To identify the source of basal IFN, we will use IFN as the readout to genetically map loci that confer basal IFN. Execution of our research plan will provide solid data for an in-depth R01 application in the future.
Type I Interferon (IFN-I) is a major player in host response to pathogen and in regulation of the immune system. In addition to induced IFN-I, there is constitutive (basal IFN) that was reported thirty years ago but has been largely ignored since then. In this proposal, we will investigate the mechanism of activation and regulation of constitutive type I IFN (basal IFN) that, according to our data, plays an important role in necroptotic cell death. In addition, we will identify genes that activate type I IFN.
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