Receptors of the tumor necrosis factor receptor (TNFR) superfamily are expressed on a wide variety of cell types, and deliver many and diverse signals affecting cell activation, differentiation, and programmed cell death. Understanding how these receptors deliver cell signals, and how this process is regulated, is important to both basic knowledge about this large and multifunctional group of receptors, as well as how these signaling pathways can be manipulated to combat autoimmune disease, malignancy, and infection. The proposed project builds upon the progress made during the present funding of this grant, to examine how the TNFR family member CD40 regulates signaling to B lymphocytes. The present proposal extends our investigations to additional members of the TNFR superfamily, including CD120b (TNFR2), CD27, and the receptors for BAFF; and to an understudied TRAF in B lymphocytes, TRAF5. The proposed experiments also investigate the potential receptor, cell type, and species specificity of receptor-induced TRAF degradation, a key regulatory mechanism for TNFR family signaling. Because all cells, particularly immune cells, express many TNFR superfamily members simultaneously and/or sequentially, we also wish to examine the mechanisms and consequences of receptor interactions in determining biological outcomes of cell signaling.
Three Aims are proposed:
Aim 1. To understand the regulation of TRAF degradation by members of the TNFR superfamily;
Aim 2. To examine how the molecular mechanisms of interactions between TNFR family members with each other and other key B cell receptors regulate B cell activation, survival and apoptosis;
Aim 3. To explore the role of TRAF5 in B cell activation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI049993-05
Application #
6965919
Study Section
Cellular and Molecular Immunology - B (CMI)
Program Officer
Miller, Lara R
Project Start
2001-09-01
Project End
2010-03-31
Budget Start
2005-07-05
Budget End
2006-03-31
Support Year
5
Fiscal Year
2005
Total Cost
$282,094
Indirect Cost
Name
University of Iowa
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Jellusova, Julia; Miletic, Ana V; Cato, Matthew H et al. (2013) Context-specific BAFF-R signaling by the NF-?B and PI3K pathways. Cell Rep 5:1022-35
Hildebrand, Joanne M; Yi, Zuoan; Buchta, Claire M et al. (2011) Roles of tumor necrosis factor receptor associated factor 3 (TRAF3) and TRAF5 in immune cell functions. Immunol Rev 244:55-74
Tseng, Wendy; Lu, Jinxiu; Bishop, Gail A et al. (2010) Regulation of interleukin-6 expression in osteoblasts by oxidized phospholipids. J Lipid Res 51:1010-6
Hildebrand, Joanne M; Luo, Zhenghua; Manske, Michelle K et al. (2010) A BAFF-R mutation associated with non-Hodgkin lymphoma alters TRAF recruitment and reveals new insights into BAFF-R signaling. J Exp Med 207:2569-79
Peters, Anna L; Bishop, Gail A (2010) Differential TRAF3 utilization by a variant human CD40 receptor with enhanced signaling. J Immunol 185:6555-62
Peters, Anna L; Stunz, Laura L; Meyerholz, David K et al. (2010) Latent membrane protein 1, the EBV-encoded oncogenic mimic of CD40, accelerates autoimmunity in B6.Sle1 mice. J Immunol 185:4053-62
Kraus, Zachary J; Nakano, Hiroyasu; Bishop, Gail A (2009) TRAF5 is a critical mediator of in vitro signals and in vivo functions of LMP1, the viral oncogenic mimic of CD40. Proc Natl Acad Sci U S A 106:17140-5
Poovassery, Jayakumar S; Vanden Bush, Tony J; Bishop, Gail A (2009) Antigen receptor signals rescue B cells from TLR tolerance. J Immunol 183:2974-83
Graham, John P; Moore, Carissa R; Bishop, Gail A (2009) Roles of the TRAF2/3 binding site in differential B cell signaling by CD40 and its viral oncogenic mimic, LMP1. J Immunol 183:2966-73
Peters, Anna L; Stunz, Laura L; Bishop, Gail A (2009) CD40 and autoimmunity: the dark side of a great activator. Semin Immunol 21:293-300

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