The major long-term objective of this program project grant is to develop mechanistic understanding of the action of Interferons (IFNs), other cytokines, and products exhibiting pathogen associated molecular patterns (PAMPs). Collectively, these molecules and their cognate cellular receptors regulate both intercellular communication and the interface between the organisms and their environment through immunomodulatory, anti-viral, anti-microbial, and anti-tumor actions. An important component of this goal has been the integration of mammalian response to viral infection and double stranded RNA (dsRNA) via Toll like receptors (TLRs) with those invoked by cytokine receptor family members. A central theme of the proposal will be to identify the means through which a relatively limited set of molecular players achieve an impressively broad and complex spectrum of cellular response patterns. This will be achieved by analysis of the novel ways in which these receptors engage both JAK/STAT and non-JAK/STAT components to achieve cell type- and stimulus-specific responses. In addition, novel receptor-independent roles for JAK/STAT members will also be explored: Project 1 will explore novel responses to IFNs that are essential in cooperation with the activation of STATs to induce the full spectrum of response. Project 2 will focus upon the role of the IFN-inducible, dsRNA activated protein kinase (PKR) in mediating responses to cytokines and TLRs. Project 3 will focus upon signaling mechanisms utilized by dsRNA and TLRS in promoting expression of IFN-inducible genes. Project 4 will consider mechanisms involved in IL-4/IL-13- and/or STAT6-dependent and -independent control of chemokine gene expression. These projects, supported by one administrative and two state of the art technology cores, will collectively provide valuable mechanistic insight into cytokine and viral actions controlling gene expression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA062220-12
Application #
7060442
Study Section
Subcommittee G - Education (NCI)
Program Officer
Mccarthy, Susan A
Project Start
1994-08-15
Project End
2010-04-30
Budget Start
2006-05-17
Budget End
2007-04-30
Support Year
12
Fiscal Year
2006
Total Cost
$1,951,862
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Herjan, Tomasz; Hong, Lingzi; Bubenik, Jodi et al. (2018) IL-17-receptor-associated adaptor Act1 directly stabilizes mRNAs to mediate IL-17 inflammatory signaling. Nat Immunol 19:354-365
Veleeparambil, Manoj; Poddar, Darshana; Abdulkhalek, Samar et al. (2018) Constitutively Bound EGFR-Mediated Tyrosine Phosphorylation of TLR9 Is Required for Its Ability To Signal. J Immunol 200:2809-2818
Nan, Jing; Wang, Yuxin; Yang, Jinbo et al. (2018) IRF9 and unphosphorylated STAT2 cooperate with NF-?B to drive IL6 expression. Proc Natl Acad Sci U S A 115:3906-3911
Sarvestani, Samaneh K; Signs, Steven A; Lefebvre, Veronique et al. (2018) Cancer-predicting transcriptomic and epigenetic signatures revealed for ulcerative colitis in patient-derived epithelial organoids. Oncotarget 9:28717-28730
Cai, Gang; Zhu, Liang; Chen, Xing et al. (2018) TRAF4 binds to the juxtamembrane region of EGFR directly and promotes kinase activation. Proc Natl Acad Sci U S A 115:11531-11536
Zhou, Hao; Bulek, Katarzyna; Li, Xiao et al. (2017) IRAK2 directs stimulus-dependent nuclear export of inflammatory mRNAs. Elife 6:
Wang, Chenhui; Zhang, Cun-Jin; Martin, Bradley N et al. (2017) IL-17 induced NOTCH1 activation in oligodendrocyte progenitor cells enhances proliferation and inflammatory gene expression. Nat Commun 8:15508
Wang, Yuxin; Nan, Jing; Willard, Belinda et al. (2017) Negative regulation of type I IFN signaling by phosphorylation of STAT2 on T387. EMBO J 36:202-212
Doherty, Mary R; Cheon, HyeonJoo; Junk, Damian J et al. (2017) Interferon-beta represses cancer stem cell properties in triple-negative breast cancer. Proc Natl Acad Sci U S A 114:13792-13797
Liu, Caini; Zhu, Liang; Fukuda, Koichi et al. (2017) The flavonoid cyanidin blocks binding of the cytokine interleukin-17A to the IL-17RA subunit to alleviate inflammation in vivo. Sci Signal 10:

Showing the most recent 10 out of 253 publications