Abstract

and specific aims): Tumor necrosis factor alpha (TNFa) has been implicated in many human disease processes especially those involving the lung as macrophages appear to be important target cells. TNFa is recognized by the cell surface receptors CD120a, (p55) and CD120b (p75). Ligation and aggregation of CD120a (p55) are necessary for the induction of the majority of cellular responses to TNFa including the induction of nitric oxide and insulin-like growth factor-1 expression by macrophages. Several signal transduction mechanisms have been reported to be activated in response to activated TNFa including a kinase cascade that mediates the activation of p42mapk/erk2. It is not known how this kinase cascade is coupled to CD120a (p55). It is hypothesized that signalling through CD120a (p55) is initiated by the phosphoproteins pp95 and/or pp120 which, through their intrinsic association with the intracellular domain of CD120a (p55), enable communication between the receptor and the distal kinase signaling cascade via RAS.
The specific aims are: 1) to purify and clone the phosphoproteins, pp95 and pp120, that are constitutively associated with the intracellular domain (ICD) of CD120a (p55); 2) to investigate the functions of pp95 and pp120 and to define the region(s) within the ICD of CD120a (p55) that interact with pp95 and pp120; and 3) to determine the upstream kinase(s) and signalling components responsible for activating p42mapk/erk2.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL055549-04
Application #
2910606
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1996-05-01
Project End
2000-04-30
Budget Start
1999-05-01
Budget End
2000-04-30
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
National Jewish Health
Department
Type
DUNS #
City
Denver
State
CO
Country
United States
Zip Code
80206

  Publications

Redente, Elizabeth F; Jacobsen, Kristen M; Solomon, Joshua J et al. (2011) Age and sex dimorphisms contribute to the severity of bleomycin-induced lung injury and fibrosis. Am J Physiol Lung Cell Mol Physiol 301:L510-8
Wynes, Murry W; Edelman, Benjamin L; Kostyk, Amanda G et al. (2011) Increased cell surface Fas expression is necessary and sufficient to sensitize lung fibroblasts to Fas ligation-induced apoptosis: implications for fibroblast accumulation in idiopathic pulmonary fibrosis. J Immunol 187:527-37
Tollefson, Angela K; Oberley-Deegan, Rebecca E; Butterfield, Kiel T et al. (2010) Endogenous enzymes (NOX and ECSOD) regulate smoke-induced oxidative stress. Free Radic Biol Med 49:1937-46
Terry Powers, Jennifer L; Mace, Kimberly E; Parfrey, Helen et al. (2010) TNF receptor-1 (TNF-R1) ubiquitous scaffolding and signaling protein interacts with TNF-R1 and TRAF2 via an N-terminal docking interface. Biochemistry 49:7821-9
Mace, Kimberly E; Lussier, Marc P; Boulay, Guylain et al. (2010) TRUSS, TNF-R1, and TRPC ion channels synergistically reverse endoplasmic reticulum Ca2+ storage reduction in response to m1 muscarinic acetylcholine receptor signaling. J Cell Physiol 225:444-53
Cha, Seung-Ick; Groshong, Steve D; Frankel, Stephen K et al. (2010) Compartmentalized expression of c-FLIP in lung tissues of patients with idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol 42:140-8
Fernandez-Boyanapalli, Ruby F; Frasch, S Courtney; McPhillips, Kathleen et al. (2009) Impaired apoptotic cell clearance in CGD due to altered macrophage programming is reversed by phosphatidylserine-dependent production of IL-4. Blood 113:2047-55
Frankel, Stephen K; Cosgrove, Gregory P; Cha, Seung-Ick et al. (2006) TNF-alpha sensitizes normal and fibrotic human lung fibroblasts to Fas-induced apoptosis. Am J Respir Cell Mol Biol 34:293-304
Kostyk, Amanda G; Dahl, Karen M; Wynes, Murry W et al. (2006) Regulation of chemokine expression by NaCl occurs independently of cystic fibrosis transmembrane conductance regulator in macrophages. Am J Pathol 169:12-20
Soond, Surinder M; Terry, Jennifer L; Riches, David W H (2006) TRUSS, a tumor necrosis factor receptor-1-interacting protein, activates c-Jun NH(2)-terminal kinase and transcription factor AP-1. FEBS Lett 580:4591-6

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