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.
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.
|Sridharan, Haripriya; Ragan, Katherine B; Guo, Hongyan et al. (2017) Murine cytomegalovirus IE3-dependent transcription is required for DAI/ZBP1-mediated necroptosis. EMBO Rep 18:1429-1441|
|Martin, Bradley N; Wang, Chenhui; Zhang, Cun-jin et al. (2016) T cell-intrinsic ASC critically promotes T(H)17-mediated experimental autoimmune encephalomyelitis. Nat Immunol 17:583-92|
|Nogusa, Shoko; Thapa, Roshan J; Dillon, Christopher P et al. (2016) RIPK3 Activates Parallel Pathways of MLKL-Driven Necroptosis and FADD-Mediated Apoptosis to Protect against Influenza A Virus. Cell Host Microbe 20:13-24|
|Antonopoulos, Christina; Russo, Hana M; El Sanadi, Caroline et al. (2015) Caspase-8 as an Effector and Regulator of NLRP3 Inflammasome Signaling. J Biol Chem 290:20167-84|
|Omoto, Shinya; Guo, Hongyan; Talekar, Ganesh R et al. (2015) Suppression of RIP3-dependent necroptosis by human cytomegalovirus. J Biol Chem 290:11635-48|
|Guo, Hongyan; Omoto, Shinya; Harris, Philip A et al. (2015) Herpes simplex virus suppresses necroptosis in human cells. Cell Host Microbe 17:243-51|
|Guo, Hongyan; Kaiser, William J; Mocarski, Edward S (2015) Manipulation of apoptosis and necroptosis signaling by herpesviruses. Med Microbiol Immunol 204:439-48|
|Kang, Seokwon; Fernandes-Alnemri, Teresa; Rogers, Corey et al. (2015) Caspase-8 scaffolding function and MLKL regulate NLRP3 inflammasome activation downstream of TLR3. Nat Commun 6:7515|
|Mocarski, Edward S; Guo, Hongyan; Kaiser, William J (2015) Necroptosis: The Trojan horse in cell autonomous antiviral host defense. Virology 479-480:160-6|
|Vanden Berghe, Tom; Kaiser, William J; Bertrand, Mathieu Jm et al. (2015) Molecular crosstalk between apoptosis, necroptosis, and survival signaling. Mol Cell Oncol 2:e975093|
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