Alternate Pathways for Interferon and Cytokine Signaling
干扰素和细胞因子信号转导的替代途径
基本信息
- 批准号:6942224
- 负责人:
- 金额:$ 25.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-07-12 至 2010-03-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
The long-term objective of this project is to understand the role of protein kinase R (PKR) in the regulation of signal
transduction pathways activated by interferons (IFNs), cytokines, and the pathogen associated molecular patterns
(PAMPS) signaling via Toll like receptors (TLRs). PKR regulates signaling in the NF-tcB pathway by different ligands
including dsRNA, tumor necrosis factor (TNF) and IFN-y via its interaction with ItcB kinase. The engagement of the
Type I and type IIIFN receptors can also lead to PKR regulation of cytosolic cPLA2 and Statl serine phosphorylation.
In addition, Stat3 tyrosine and serine phosphorylation can be regulated via a PKR-dependent pathway. PAMP
engagement of TLRs also activates PKR-dependent regulation of the production of pro-inflammatory cytokines via a
mitogen activated protein kinase (MAPK) pathway where PKR interacts with MAP kinase kinase 6 (MKK6). Our
discoveries that dsRNA can regulate tumor suppressor p53 stability and that dsRNA and CpG oligodeoxynucleotides
(CpG ODN) can synergize in pro-inflammatory cytokine production raises questions about a role for PKR. We propose
to provide a better understanding of the molecular determinants that regulate these pathways. More specifically we will
focus on the role of PKR as a key signaling molecule that can be invoked by IFNs, cytokines, and PAMPs to signal
different transcription factors regulating gene expression. We will achieve this by the following specific aims. We will
establish the molecular determinants that define PKR as a key regulator of MAPK signaling pathways. We will
investigate the mechanisms of p53 instability induced by dsRNA and characterize the signaling.pathway by which this
is achieved. We will define the mechanisms of synergy between dsRNA and CpG ODN by investigating the role of
type I IFNs, dsRNA signaling pathways, and components of the TLR signaling pathway required to mediate the
synergistic response. We will also determine whether the synergy results in enhanced tumor immunity in vivo and
establish the relative contribution of the dsRNA-activated pathways. These studies have the potential to provide insight
into the regulation of innate immunity and its exploitation in cancer therapy.
本项目的长期目标是了解蛋白激酶R(PKR)在信号调节中的作用
由干扰素(IFN)、细胞因子激活的转导途径和病原体相关分子模式
(PAMPS)通过Toll样受体(TLR)信号传导。PKR通过不同配体调节NF-tcB通路中的信号传导
包括dsRNA、肿瘤坏死因子(TNF)和IFN-γ,通过其与ItcB激酶的相互作用。的接合
I型和III型IFN受体也可导致胞质cPLA 2和Statl丝氨酸磷酸化的PKR调节。
此外,Stat 3酪氨酸和丝氨酸磷酸化可以通过PKR依赖性途径调节。PAMP
TLR的参与也通过激活PKR依赖性调节促炎细胞因子的产生,
丝裂原活化蛋白激酶(MAPK)途径,其中PKR与MAP激酶激酶6(MKK 6)相互作用。我们
发现dsRNA可以调节肿瘤抑制因子p53的稳定性,并且dsRNA和CpG寡脱氧核苷酸
(CpG ODN)可以协同促炎细胞因子的产生,这引起了关于PKR作用的问题。我们提出
以提供对调节这些途径的分子决定因素的更好理解。更具体地说,
关注PKR作为一种关键信号分子的作用,它可以被IFN、细胞因子和PAMP激活,
不同的转录因子调节基因表达。我们将通过以下具体目标实现这一目标。我们将
确定PKR作为MAPK信号通路关键调节因子的分子决定因素。我们将
研究dsRNA诱导的p53不稳定性的机制,并表征其信号通路。
实现了。我们将通过研究dsRNA和CpG ODN之间的协同作用,
I型IFN、dsRNA信号传导途径和TLR信号传导途径的组分需要介导
协同反应。我们还将确定协同作用是否导致体内增强的肿瘤免疫,
确定dsRNA激活途径的相对贡献。这些研究有可能提供洞察力,
天然免疫的调节及其在癌症治疗中的应用。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Bryan R. G. Williams其他文献
Synthesis and breakdown of pppA2'p5'A2'p5'A and transient inhibiton of protein synthesis in extracts from interferon-treated and control cells.
干扰素处理和对照细胞提取物中 pppA2p5A2p5A 的合成和分解以及蛋白质合成的瞬时抑制。
- DOI:
- 发表时间:
1978 - 期刊:
- 影响因子:0
- 作者:
Bryan R. G. Williams;I. M. Kerr;Christopher S. Gilbert;Carol N. White;L. Ball - 通讯作者:
L. Ball
Translational control perks up
翻译调控活跃起来
- DOI:
10.1038/16586 - 发表时间:
1999-01-21 - 期刊:
- 影响因子:48.500
- 作者:
Robert H. Silverman;Bryan R. G. Williams - 通讯作者:
Bryan R. G. Williams
Analysis of the wilms tumor suppressor gene WT1 in endometrial carcinoma
子宫内膜癌中Wilms抑癌基因WT1的分析
- DOI:
- 发表时间:
1995 - 期刊:
- 影响因子:0
- 作者:
R. Rackley;G. Casey;Xiaolei Zhao;David W. Miller;Bryan R. G. Williams;M. Coppes - 通讯作者:
M. Coppes
Molecular characterization of cytogenetic alterations associated with the Beckwith-Wiedemann syndrome (BWS) phenotype refines the localization and suggests the gene for BWS is imprinted.
与 Beckwith-Wiedemann 综合征 (BWS) 表型相关的细胞遗传学改变的分子特征完善了定位,并表明 BWS 基因已被印记。
- DOI:
10.1093/hmg/2.5.549 - 发表时间:
1993 - 期刊:
- 影响因子:3.5
- 作者:
R. Weksberg;I. Teshima;Bryan R. G. Williams;C. Greenberg;S. Pueschel;J. Chernos;S. B. Fowlow;E. Hoyme;I. Anderson;D. Whiteman;N. Fisher;J. Squire - 通讯作者:
J. Squire
Antisense transcripts and protein binding motifs within the Wilms tumour (WT1) locus.
Wilms 肿瘤 (WT1) 基因座内的反义转录物和蛋白质结合基序。
- DOI:
- 发表时间:
1994 - 期刊:
- 影响因子:8
- 作者:
C. Campbell;A. Huang;A. Gurney;P. Kessler;J. A. Hewitt;Bryan R. G. Williams - 通讯作者:
Bryan R. G. Williams
Bryan R. G. Williams的其他文献
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{{ truncateString('Bryan R. G. Williams', 18)}}的其他基金
INTEGRATED PROTEOM WORKS SYSTEM: CANCER, PROSTATE & BREAST CANCER
综合蛋白质工作系统:癌症、前列腺
- 批准号:
7166142 - 财政年份:2005
- 资助金额:
$ 25.57万 - 项目类别:
INTEGRATED PROTEOM WORKS SYSTEM: CARDIOVASCULAR DISEASE
综合蛋白质工作系统:心血管疾病
- 批准号:
7166141 - 财政年份:2005
- 资助金额:
$ 25.57万 - 项目类别:
Pilot: Regulation of Obesity and ER Stress by Salicylates
试点:水杨酸盐调节肥胖和内质网应激
- 批准号:
7007855 - 财政年份:2005
- 资助金额:
$ 25.57万 - 项目类别:
INTEGRATED PROTEOM WORKS SYSTEM: ASTHMA, IMMUNOLOGY
综合蛋白质工作系统:哮喘、免疫学
- 批准号:
7166143 - 财政年份:2005
- 资助金额:
$ 25.57万 - 项目类别:
ALTERNATE PATHWAYS FOR INTERFERON AND CYTOKINE SIGNALING
干扰素和细胞因子信号转导的替代途径
- 批准号:
6580345 - 财政年份:2002
- 资助金额:
$ 25.57万 - 项目类别:
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