Programmed necrosis is a regulated form of cell death directed by the kinases RIP1 and RIP3. A number of cell stress and host defense pathways prime cells for this programmed necrosis, and in the context of viral infection, elimination of infected cells benefits the host;however, when dysregulated necrosis promotes inflammation and potentially drives a range of disease states. At present, the signaling networks control by RIP1 and RIP3 kinases remain unclear. The NIH Director's Early Independence Award will enable me to establish a research program to define the molecular basis of necrosis. To generate a comprehensive picture, we will (1) characterize the signal transduction pathways upstream and downstream of RIP1 and RIP3, (2) identify new signaling components, (3) develop strategies for therapeutic intervention, and (4) extend these finding to genetic mouse models of inflammation caused by excessive cell death. These studies will contribute to our ability to treat disease through suppressing or altering cell death modalities.

Public Health Relevance

The current project focuses on defining the role of RIP1 and RIP3 kinases in inflammation and programmed cell death following activation of death receptor and pathogen recognition receptor pathways. Disease caused by dysregulation of these kinases as well as pathogen subversion strategies will be examined. The design of novel therapies to modulate necrotic cell death will emerge from a more defined understanding of RIP kinases in host defence and in controlling cell fate.

National Institute of Health (NIH)
Early Independence Award (DP5)
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Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Basavappa, Ravi
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Emory University
Schools of Medicine
United States
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Mocarski, Edward S; Kaiser, William J; Livingston-Rosanoff, Devon et al. (2014) True grit: programmed necrosis in antiviral host defense, inflammation, and immunogenicity. J Immunol 192:2019-26
Berger, Scott B; Kasparcova, Viera; Hoffman, Sandy et al. (2014) Cutting Edge: RIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice. J Immunol 192:5476-80
Rickard, James A; Anderton, Holly; Etemadi, Nima et al. (2014) TNFR1-dependent cell death drives inflammation in Sharpin-deficient mice. Elife 3:
Kaiser, William J; Daley-Bauer, Lisa P; Thapa, Roshan J et al. (2014) RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition. Proc Natl Acad Sci U S A 111:7753-8
Kaiser, William J; Sridharan, Haripriya; Huang, Chunzi et al. (2013) Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL. J Biol Chem 288:31268-79
Antonopoulos, Christina; El Sanadi, Caroline; Kaiser, William J et al. (2013) Proapoptotic chemotherapeutic drugs induce noncanonical processing and release of IL-1* via caspase-8 in dendritic cells. J Immunol 191:4789-803
Kaiser, William J; Upton, Jason W; Mocarski, Edward S (2013) Viral modulation of programmed necrosis. Curr Opin Virol 3:296-306