The overall goal of this research program is to understand how the death domain kinase RIP mediates signal transduction by the proinflammatory cytokine, tumor necrosis factor (TNF). The potent biological action of TNF has been studied in detail and known to contribute to sepsis, inflammation and cancer. TNF activates multiple transduction pathways including the NF-kappaB, SAPK/JNK and p38 MAP kinase pathways. RIP is the only known serine/threonine kinase recruited to the tumor necrosis factor receptor (TNFR1) upon receptor activation. Yet the function of the kinase activity of RIP is unknown. The contribution of the kinase activity of RIP to mammalian development and to TNF signal transduction will be investigated. To assess RIP function in TNF signaling, we created RIP-deficient mice. In the absence of RIP, mice exhibit postnatal lethality and apoptosis of the immune, adipocyte and muscle lineages. A specific focus of this proposal is to understand whether the RIP- associated lethality and tissue apoptosis is TNF-mediated. The RIP-deficient phenotype contrasts sharply with that of the TNF alphaminus/minus or TNFR1minus/minus mice, which are for the most part normal. These studies suggest that RIP may have additional biologic roles beyond that of TNF signaling. RIP interacts with other TNFR1-related death receptors (DR3, DR4 and DR5). An additional objective of this proposal is to determine the functional contribution of RIP to signaling by these death receptors and to identify the biological processes regulated by these death receptor pathways in lymphocytes. Our genetic analysis revealed a critical role for RIP in the NF- kappaB response to TNF. Our preliminary studies suggest that RIP may also contribute to the p38 MAP kinase pathway. The molecular mechanisms of RIP mediated NF-kappaB and p38 MAP kinase activation will be investigated.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM061298-03
Application #
6520249
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Marino, Pamela
Project Start
2000-03-01
Project End
2005-02-28
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
3
Fiscal Year
2002
Total Cost
$117,000
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Genetics
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655