: Arthritis is a class of disease that affects 43 million Americans. The causes of arthritis are, in general, unknown. However, dysregulated inflammatory and immune responses apparently play very important roles in these diseases, since many types of arthritis involve chronic inflammation in different organs. Tumor necrosis factor alpha (TNFalpha) is a pro-inflammatory cytokine and plays an important role in the inflammatory processes of rheumatoid arthritis. Although TNFalpha is required for regulation of normal inflammatory and immune responses, acute elevated levels of TNFalpha may lead to septic shock during bacterial infection, while chronically elevated levels of TNFalpha are associated with the inflammatory processes of rheumatoid arthritis. Elevated levels of TNFalpha induce expression of many inflammatory genes. Expression of these genes is thought to elicit the swelling, pain and other effects of rheumatoid arthritis. Inhibition of TNFalpha function in vitro and in vivo has been shown to affect several animal models of inflammation. Modulation of TNFalpha levels has also been shown to reduce signs and symptoms of severely active rheumatoid arthritis patients. Thus, understanding the molecular mechanism of TNFalpha function will provide more therapeutic approaches for treatment of arthritic diseases. The present proposal seeks to apply molecular tools to elucidate the precise TNFalpha signaling pathway that leads to activation of NF-kB, a major transcription factor that controls the expression of various inflammatory genes. Specifically, we will investigate how RIP, a key signaling intermediate in the TNFalpha pathway, transmits TNFalpha signals to activate NF-kB. We will also examine how TNFalpha -induced signaling pathway is negatively regulated. Finally, we will use genetic complementation approaches to identify unknown signaling components that are required for TNFalpha -induced NF-kB activation. These studies will provide essential new information about the molecular mechanisms by which TNFalpha signals are transmitted to downstream components that activate the NF-kB family of transcription factors controlling expression of inflammatory genes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050848-02
Application #
6640175
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Johnson, David R
Project Start
2002-07-01
Project End
2007-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
2
Fiscal Year
2003
Total Cost
$267,547
Indirect Cost
Name
State University of New York at Buffalo
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Jiang, Changying; Zhou, Zhicheng; Quan, Yanping et al. (2016) CARMA3 Is a Host Factor Regulating the Balance of Inflammatory and Antiviral Responses against Viral Infection. Cell Rep 14:2389-401
Blonska, Marzenna; Zhu, Yifan; Chuang, Hubert H et al. (2015) Jun-regulated genes promote interaction of diffuse large B-cell lymphoma with the microenvironment. Blood 125:981-91
Zhao, Xue-Qiang; Zhu, Le-Le; Chang, Qing et al. (2014) C-type lectin receptor dectin-3 mediates trehalose 6,6'-dimycolate (TDM)-induced Mincle expression through CARD9/Bcl10/MALT1-dependent nuclear factor (NF)-?B activation. J Biol Chem 289:30052-62
Wang, Huafeng; LeBert, Vanessa; Hung, Chiung Yu et al. (2014) C-type lectin receptors differentially induce th17 cells and vaccine immunity to the endemic mycosis of North America. J Immunol 192:1107-1119
Yang, M; Shao, J-H; Miao, Y-J et al. (2014) Tumor cell-activated CARD9 signaling contributes to metastasis-associated macrophage polarization. Cell Death Differ 21:1290-302
Jia, Xin-Ming; Tang, Bing; Zhu, Le-Le et al. (2014) CARD9 mediates Dectin-1-induced ERK activation by linking Ras-GRF1 to H-Ras for antifungal immunity. J Exp Med 211:2307-21
Cheng, Qianqian; Zhang, Qingfeng; Xu, Xindong et al. (2014) MAPK phosphotase 5 deficiency contributes to protection against blood-stage Plasmodium yoelii 17XL infection in mice. J Immunol 192:3686-96
Zhong, Bo; Liu, Xikui; Wang, Xiaohu et al. (2013) Ubiquitin-specific protease 25 regulates TLR4-dependent innate immune responses through deubiquitination of the adaptor protein TRAF3. Sci Signal 6:ra35
Liu, Xikui; Li, Hongxiu; Zhong, Bo et al. (2013) USP18 inhibits NF-?B and NFAT activation during Th17 differentiation by deubiquitinating the TAK1-TAB1 complex. J Exp Med 210:1575-90
Zhu, Le-Le; Zhao, Xue-Qiang; Jiang, Changying et al. (2013) C-type lectin receptors Dectin-3 and Dectin-2 form a heterodimeric pattern-recognition receptor for host defense against fungal infection. Immunity 39:324-34

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