Role of RNase L in the Biology of Prostate Cancer
RNase L 在前列腺癌生物学中的作用
基本信息
- 批准号:7008850
- 负责人:
- 金额:$ 30.63万
- 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:2004-02-16 至 2009-01-31
- 项目状态:已结题
- 来源:
- 关键词:RNA interferenceandrogensapoptosisbiological signal transductioncell growth regulationcell lineclinical researchendoribonucleasesenzyme activityenzyme inhibitorsfluorescence resonance energy transfergenetically modified animalshuman subjectinterferonslaboratory mousemicroarray technologyneoplastic cellprostate neoplasmstumor suppressor proteins
项目摘要
DESCRIPTION (provided by applicant): Recently, the interferon (IFN) antiviral pathways and prostate cancer genetics and have surprisingly converged on ribonuclease L (RNase L), a uniquely regulated enzyme that requires 5'-triphosphoryl, 2',5'- linked oligoadenylates (2-5A) for its activity. The presence of both germline mutations in RNASEL segregating with disease within hereditary prostate cancer 1 (HPC1)-affected families and loss of heterozygosity (LOH) in tumor tissues point to a novel role for RNase L in the pathogenesis of prostate cancer. Our preliminary data implicate RNase L in mediating prostate cancer cell apoptosis and suggest that RNase L functions as a tumor suppressor in mice. We propose to study the fundamental role of RNase L in prostate cancer using cell culture and animal models and in RNA isolated from prostate cancer patients. Our hypothesis is that RNase L suppresses development of prostate cancer by affecting the balance between cell growth and apoptosis. Our specific aims are to: (1) study regulation of the 2-5A/RNase L system by IFN and androgen in prostate cancer cells and to identify viral and/or cellular RNA activators of 2-5A synthetase in prostate tumor RNA; (2) downregulate RNase L and RNase L inhibitor (RLI) levels with short interfering RNAs (siRNAs) in prostate cancer cells prior to viral infection, dsRNA treatment or androgen deprivation and probe the apoptotic signaling pathway; and (3) study the effect of RNase L on prostate biology in mice that are wild type or deficient in RNASEL in combination with loss of other genes implicated in prostate cancer pathogenesis (p53 and NKX3.1) or dsRNA mediated apoptosis (protein kinase PKR).
Mapping of HPC1 to RNASEL and the association of RNASEL mutations with prostate cancer risk provide the justification for these studies. The experiments described in this PROPOSAL describe a previously unexplored area of research that may bring us closer to the eventual goal of understanding a molecular basis for prostate cancer.
描述(由申请人提供):最近,干扰素(IFN)抗病毒途径和前列腺癌遗传学令人惊讶地集中在核糖核酸酶L(RNase L)上,核糖核酸酶L是一种独特调节的酶,其活性需要5 ′-三磷酰基、2 ′,5 ′-连接的寡腺苷酸(2-5A)。在遗传性前列腺癌1(HPC 1)影响的家族中,RNASEL中存在两种种系突变与疾病分离,肿瘤组织中存在杂合性缺失(洛),这表明RNA酶L在前列腺癌发病机制中具有新的作用。我们的初步数据暗示RNase L在介导前列腺癌细胞凋亡,并建议RNase L作为一种肿瘤抑制剂在小鼠中的功能。我们建议使用细胞培养和动物模型以及从前列腺癌患者中分离的RNA来研究RNase L在前列腺癌中的基本作用。我们的假设是RNase L通过影响细胞生长和凋亡之间的平衡来抑制前列腺癌的发展。我们的具体目标是:(1)研究前列腺癌细胞中IFN和雄激素对2-5A/RNase L系统的调节,并鉴定前列腺肿瘤RNA中2-5A合成酶的病毒和/或细胞RNA激活剂;(2)在病毒感染前用短干扰RNA(siRNA)下调前列腺癌细胞中的RNA酶L和RNA酶L抑制剂(RLI)水平,dsRNA处理或雄激素剥夺并探测凋亡信号通路;和(3)研究RNase L对野生型或RNASEL缺陷的小鼠中前列腺生物学的作用,所述小鼠与前列腺癌发病机制中涉及的其它基因的缺失组合1)或dsRNA介导的细胞凋亡(蛋白激酶PKR)。
HPC 1与RNASEL的映射以及RNASEL突变与前列腺癌风险的相关性为这些研究提供了理由。本提案中描述的实验描述了一个以前未探索的研究领域,可能使我们更接近了解前列腺癌分子基础的最终目标。
项目成果
期刊论文数量(0)
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Robert H. Silverman其他文献
17 PKR-dependent Regulation of IL-10 in Response to Double-stranded RNA
- DOI:
10.1016/j.cyto.2007.07.022 - 发表时间:
2007-07-01 - 期刊:
- 影响因子:
- 作者:
Arindam Chakrabarti;Anthony J. Sadler;Robert H. Silverman;Bryan R.G. Williams - 通讯作者:
Bryan R.G. Williams
Durch interferon stimulierte und reprimierte gene
Durch干扰素刺激和重新启动基因
- DOI:
- 发表时间:
1999 - 期刊:
- 影响因子:0
- 作者:
Robert H. Silverman;Bryan R. G. Williams;Sandy D. Der - 通讯作者:
Sandy D. Der
ID: 206: RNase L activates the NLRP3 inflammasome during viral infections
- DOI:
10.1016/j.cyto.2015.08.210 - 发表时间:
2015-11-01 - 期刊:
- 影响因子:
- 作者:
Shuvojit Banerjee;Arindam Chakrabarti;Luigi Franchi;Yueh-Ming Loo;Michael Gale;Gabriel Nunez;Robert H. Silverman - 通讯作者:
Robert H. Silverman
The ppp(A2'p)nA and protein kinase systems in wild-type and interferon-resistant Daudi cells.
野生型和抗干扰素 Daudi 细胞中的 ppp(A2p)nA 和蛋白激酶系统。
- DOI:
- 发表时间:
2005 - 期刊:
- 影响因子:0
- 作者:
Robert H. Silverman;D. Watling;Frances R. Balkwill;John Trowsdale;Ian M. Kerr - 通讯作者:
Ian M. Kerr
167: Host and viral 2′,5′-phosphodiesterases antagonize DsRNA signaling to RNase L during antiviral innate immunity
- DOI:
10.1016/j.cyto.2014.07.174 - 发表时间:
2014-11-01 - 期刊:
- 影响因子:
- 作者:
Robert H. Silverman;Susan R. Weiss - 通讯作者:
Susan R. Weiss
Robert H. Silverman的其他文献
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{{ truncateString('Robert H. Silverman', 18)}}的其他基金
ANTIVIRAL MECHANISMS OF 2-5A-DEPENDENT RNASE L
2-5A依赖性RNA酶L的抗病毒机制
- 批准号:
9761446 - 财政年份:2017
- 资助金额:
$ 30.63万 - 项目类别:
ANTIVIRAL MECHANISMS OF 2-5A-DEPENDENT RNASE L
2-5A依赖性RNA酶L的抗病毒机制
- 批准号:
10005110 - 财政年份:2017
- 资助金额:
$ 30.63万 - 项目类别:
Control of Viral Pathogenesis by Regulation of 2-5A Levels
通过调节 2-5A 水平控制病毒发病机制
- 批准号:
8784188 - 财政年份:2013
- 资助金额:
$ 30.63万 - 项目类别:
Control of Viral Pathogenesis by Regulation of 2-5A Levels
通过调节 2-5A 水平控制病毒发病机制
- 批准号:
10077787 - 财政年份:2013
- 资助金额:
$ 30.63万 - 项目类别:
Control of Viral Pathogenesis by Regulation of 2-5A Levels
通过调节 2-5A 水平控制病毒发病机制
- 批准号:
8974219 - 财政年份:2013
- 资助金额:
$ 30.63万 - 项目类别:
Control of Viral Pathogenesis by Regulation of 2-5A Levels
通过调节 2-5A 水平控制病毒发病机制
- 批准号:
10310409 - 财政年份:2013
- 资助金额:
$ 30.63万 - 项目类别:
Control of Viral Pathogenesis by Regulation of 2-5A Levels
通过调节 2-5A 水平控制病毒发病机制
- 批准号:
8476886 - 财政年份:2013
- 资助金额:
$ 30.63万 - 项目类别:
Control of Viral Pathogenesis by Regulation of 2-5A Levels
通过调节 2-5A 水平控制病毒发病机制
- 批准号:
10540316 - 财政年份:2013
- 资助金额:
$ 30.63万 - 项目类别:
Control of Viral Pathogenesis by Regulation of 2-5A Levels
通过调节 2-5A 水平控制病毒发病机制
- 批准号:
9191335 - 财政年份:2013
- 资助金额:
$ 30.63万 - 项目类别:
Control of Viral Pathogenesis by Regulation of 2-5A Levels
通过调节 2-5A 水平控制病毒发病机制
- 批准号:
8601426 - 财政年份:2013
- 资助金额:
$ 30.63万 - 项目类别:
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