PROTEIN KINASE C AND COLON CARCINOGENESIS
蛋白激酶 C 与结肠癌发生
基本信息
- 批准号:6350379
- 负责人:
- 金额:$ 33.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1999
- 资助国家:美国
- 起止时间:1999-04-02 至 2004-01-31
- 项目状态:已结题
- 来源:
- 关键词:adenomatous polyps cell line cell proliferation cellular oncology chemical carcinogenesis colon neoplasms dietary lipid disease /disorder model gastrointestinal epithelium gene expression gene mutation genetically modified animals isozymes laboratory mouse nutrition related neoplasm /cancer nutrition related tag protein kinase C tumor suppressor genes
项目摘要
Colon carcinogenesis is a complex, multi-step process involving
progressive changes in intestinal epithelial cell proliferation,
differentiation and programmed death. Our long-term goal is to
understand the role of protein kinase C (PKC) isozymes in intestinal
epithelial cell biology and colon carcinogenesis. Several lines of
evidence suggest that the PKC betaII isozyme (PKC betaII) is involved
in colon carcinogenesis. First, PKC betaII levels and activity are
elevated in colon carcinomas compared to normal colonic epithelium.
Second, PKC betaII is involved in colon carcinoma cell proliferation in
vitro. Third, components of a high fat diet can potently stimulate
intestinal epithelial cell PKC betaII activity and promote colon
carcinogenesis. Based on these findings, and our preliminary studies,
we hypothesize that PKC betaII is directly involved in colon
carcinogenesis. To directly test this hypothesis, we developed
transgenic mice that express elevated PKC betaII levels in the
intestinal epithelium. In preliminary studies, these mice exhibit
evidence of colonic epithelial hyperproliferation and an increased
susceptibility to carcinogen-induced colon cancer. In this application
we propose four specific aims to: 1) characterize three transgenic PKC
betaII lines for transgene copy number, tissue distribution, expression
level and activity of the PKC betaII transgene, and for changes in
intestinal epithelial cytokinetics; 2) assess whether transgenic PKC
betaII mice exhibit increased susceptibility to carcinogen-induced colon
cancer; 3) determine whether a high fat diet enhances the susceptibility
of transgenic PKC betaII mice to colon cancer; and 4) determine whether
elevated PKC betaII expression synergizes with loss-of-function mutation
of the APC tumor suppressor gene in promoting intestinal tumorigenesis
in the APCmin mouse model. These studies will allow the first direct
analysis of the role of PKC betaII in colon cancer in two relevant
animal models of the human disease.
结肠癌的发生是一个复杂的多步骤过程,
肠上皮细胞增殖的进行性变化,
分化和程序性死亡。 我们的长期目标是
了解蛋白激酶C(PKC)同工酶在肠道
上皮细胞生物学和结肠癌发生。几行
有证据表明,PKC β II同工酶(PKC β II)
在结肠癌发生中的作用 首先,PKC β II水平和活性是
与正常结肠上皮相比,在结肠癌中升高。
第二,PKC β II参与结肠癌细胞增殖,
体外 第三,高脂肪饮食的成分可以有效地刺激
肠上皮细胞PKC β II活性促进结肠
致癌作用 基于这些发现和我们的初步研究,
我们假设PKC β II直接参与结肠癌的发生,
致癌作用 为了直接验证这一假设,我们开发了
转基因小鼠表达升高的PKC β II水平,
肠上皮 在初步研究中,这些小鼠表现出
结肠上皮细胞过度增殖的证据,
对致癌物诱发的结肠癌的易感性。 本申请中
我们提出了四个具体的目标:1)表征三个转基因PKC
用于转基因拷贝数、组织分布、表达的β II系
PKC β II转基因的水平和活性,以及
肠上皮细胞凋亡; 2)评估转基因PKC是否
β II小鼠对致癌物诱导的结肠癌表现出增加的易感性
癌症; 3)确定高脂肪饮食是否会增加易感性
转基因PKC β II小鼠的结肠癌;和4)确定是否
PKC β II表达升高与功能缺失突变协同作用
APC抑癌基因在促进肠道肿瘤发生中的作用
APCmin小鼠模型。这些研究将允许第一个直接
分析PKC β II在结肠癌中的作用,
人类疾病的动物模型。
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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Alan P. Fields其他文献
Activation of Na/H exchanger in mesangial cells is associated with translocation of PKC isoforms.
系膜细胞中 Na/H 交换器的激活与 PKC 亚型的易位相关。
- DOI:
10.1152/ajprenal.1993.265.1.f53 - 发表时间:
1993 - 期刊:
- 影响因子:0
- 作者:
R. Saxena;B. A. Saksa;Alan P. Fields;M. B. Ganz - 通讯作者:
M. B. Ganz
A Role for Nuclear Phosphatidylinositol-specific Phospholipase C in the G<sub>2</sub>/M Phase Transition
- DOI:
10.1074/jbc.272.42.26313 - 发表时间:
1997-10-17 - 期刊:
- 影响因子:
- 作者:
Bin Sun;Nicole R. Murray;Alan P. Fields - 通讯作者:
Alan P. Fields
Alan P. Fields的其他文献
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{{ truncateString('Alan P. Fields', 18)}}的其他基金
Investigating cells of origin and oncogenic modifiers of 3q26-driven LUSC
研究 3q26 驱动的 LUSC 的起源细胞和致癌修饰因子
- 批准号:
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- 资助金额:
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A Genetically Tractable Mouse Model for PRKCI-driven Lung Squamous Cell Carcinoma
PRKCI 驱动的肺鳞状细胞癌的遗传易控制小鼠模型
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10653913 - 财政年份:2021
- 资助金额:
$ 33.5万 - 项目类别:
A Genetically Tractable Mouse Model for PRKCI-driven Lung Squamous Cell Carcinoma
PRKCI 驱动的肺鳞状细胞癌的遗传易控制小鼠模型
- 批准号:
10296271 - 财政年份:2021
- 资助金额:
$ 33.5万 - 项目类别:
A Genetically Tractable Mouse Model for PRKCI-driven Lung Squamous Cell Carcinoma
PRKCI 驱动的肺鳞状细胞癌的遗传易控制小鼠模型
- 批准号:
10413236 - 财政年份:2021
- 资助金额:
$ 33.5万 - 项目类别:
Therapeutic targeting of Kras-driven Lung Adenocarcinoma
Kras 驱动的肺腺癌的治疗靶向
- 批准号:
9303312 - 财政年份:2016
- 资助金额:
$ 33.5万 - 项目类别:
The pathophysiology and palliation of the paclitaxel-induced acute pain syndrome
紫杉醇诱发的急性疼痛综合征的病理生理学和缓解作用
- 批准号:
8930932 - 财政年份:2014
- 资助金额:
$ 33.5万 - 项目类别:
Combined PKCiota and mTOR inhibition for treatment of advanced squamous lung canc
联合 PKCiota 和 mTOR 抑制治疗晚期鳞状肺癌
- 批准号:
8299006 - 财政年份:2011
- 资助金额:
$ 33.5万 - 项目类别:
Combined PKCiota and mTOR inhibition for treatment of advanced squamous lung canc
联合 PKCiota 和 mTOR 抑制治疗晚期鳞状肺癌
- 批准号:
8110919 - 财政年份:2011
- 资助金额:
$ 33.5万 - 项目类别:
Atypical PKC signaling in lung cancer stem cells
肺癌干细胞中的非典型 PKC 信号传导
- 批准号:
8244684 - 财政年份:2010
- 资助金额:
$ 33.5万 - 项目类别:
Atypical PKC signaling in lung cancer stem cells
肺癌干细胞中的非典型 PKC 信号传导
- 批准号:
8100459 - 财政年份:2010
- 资助金额:
$ 33.5万 - 项目类别:
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