This program project grant application involves studies of the mechanisms by which several members of the Tumor Necrosis Factor Receptor (TNF-R) family transduce signals that can result in induction of apoptosis or promotion of cell survival. All TNF-family receptors have in common the ability to regulate cell life and death. Little is currently known however about the early biochemical events regulated by most TNF family receptors. Some TNF family receptors, including p60-TNF-R1, Fas, and receptors for Lymphotoxin-beta (LTbeta), are known to induce cell death when triggered by ligand through mechanisms that require neither new RNA production nor protein synthesis. However, not all cells are sensitive to the induction of cell death by these receptors, arguing that intracellular events that occur after ligand binding modulate the ability of these receptors to activate cell death pathways. Conversely, the p75-Nerve Growth Factor Receptor (NGF-R) and CD40 produce signals that promote cell survival when triggered by ligand, but the unliganded receptors paradoxically induce apoptosis. Participants in the program have identified putative signal transducing proteins that associate with the cytoplasmic domains of Fas, LTbeta receptors and CD40, including a tyrosine phosphatase and a novel TRAF- domain protein. A role for Ras-family GTPases and production of ceramide by acidic sphingomyelin in the induction of apoptosis by Fas has also been demonstrated by participants in the project. Using these and other molecules as focal points for investigation, attempts will be made to delineate the early biochemical events through which TNF family receptors trigger apoptosis and thus contribute to inflammatory, autoimmune, and neurodegenerative diseases. The central question that this program will attempt to address is whether common mechanisms are utilized by TNF-R1, Fas, LTbeta, p75-NGF-R and CD40 to either induce or inhibit apoptosis. The information derived from these studies could contribute to novel therapies for cancer, immune disorders, and neurodegenerative diseases.
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