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.

Agency
National Institute of Health (NIH)
Type
Early Independence Award (DP5)
Project #
5DP5OD012198-03
Application #
8734277
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Basavappa, Ravi
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Emory University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Weng, Dan; Marty-Roix, Robyn; Ganesan, Sandhya et al. (2014) Caspase-8 and RIP kinases regulate bacteria-induced innate immune responses and cell death. Proc Natl Acad Sci U S A 111:7391-6

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