CERAMIDE AS AN INTRA-CELLULAR MEDIATOR
神经酰胺作为细胞内介质
基本信息
- 批准号:3085965
- 负责人:
- 金额:$ 7.73万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1992
- 资助国家:美国
- 起止时间:1992-08-20 至 1997-07-31
- 项目状态:已结题
- 来源:
- 关键词:biological signal transduction cell differentiation ceramides enzyme activity gel electrophoresis gene expression genetic transcription glioma growth inhibitors myelogenous leukemia neoplastic cell northern blottings phosphatase inhibitor phosphoprotein phosphatase protein structure function protooncogene radiotracer second messengers tissue /cell culture tumor necrosis factor alpha vitamin D
项目摘要
The long term goals of this project are to understand the molecular
mechanisms of cell differentiation and proliferation. The sponsor's lab
has recently identified a novel signalling pathway whereby Vitamin D3 and
TNF-alpha were shown to activate a neutral sphingomyelinase which cleaves
sphingomyelin into Ceramide and cholinephosphate. Ceramide is capable of
inhibiting cell growth and inducing differentiation. Based on our recent
finding that Ceramide down regulates c-myc, the following hypothesis will
be investigated: Ceramide is an intracellular mediator of TNF-alpha's
activity in down-regulating c-myc, inhibiting cell proliferation, and
inducing differentiation. The specific aims of this project are therefore:
1. To define the physiologic role of Ceramide as a second messenger
involved in c-myc regulation. Planned objectives include a) demonstrating
Ceramide generation in response to TNF-alpha using a sensitive and
quantitative enzymatic assay; b) establishing the effects of Ceramide on c-
myc down-regulation using Northern Blot analysis; and c) confirming that
the mechanism of Ceramide on c-myc down-regulation is analogous to that of
TNF-alpha using Actinomycin D and nuclear run--on assays. 2. To delineate
Ceramide's mechanism of action. Since preliminary work suggests Ceramide
activates a protein phosphatase, the objectives include determining a) the
effects of Ceramide on endogenous protein phosphorylation using 2D
electrophoresis; b) the ability of Ceramide to activate a protein
phosphatase; c) structure-function activity of Ceramide analogs in
activating phosphatase and in down-regulating c-myc; and d) the effects of
phosphatase inhibitors on Ceramide's and TNF-alpha's actions. It is hoped
that these studies will define a novel signaling pathway that may disclose
important therapeutic targets for modulation of cell proliferation and
differentiation.
这个项目的长期目标是了解分子
细胞分化和增殖的机制。赞助商的实验室
最近发现了一种新的信号通路,通过这种途径,维生素D3和
肿瘤坏死因子-α被证明能激活一种中性的鞘磷脂酶,这种酶能裂解
神经鞘磷脂转化为神经酰胺和磷酸胆碱。神经酰胺能够
抑制细胞生长,诱导分化。根据我们最近的调查
发现神经酰胺下调c-myc,下面的假设将
有待研究:神经酰胺是肿瘤坏死因子-α的细胞内介质
下调c-myc活性,抑制细胞增殖,以及
诱导分化。因此,该项目的具体目标是:
1.确定神经酰胺作为第二信使的生理作用
参与c-myc的调控。计划的目标包括a)演示
神经酰胺的产生对肿瘤坏死因子-α的反应
定量酶分析;b)建立神经酰胺对C-反应的影响。
使用Northern Blot分析MYC下调;以及c)确认
神经酰胺下调c-myc的机制与神经酰胺类似。
肿瘤坏死因子-α放线菌素D和核连续检测。2.划定
神经酰胺的作用机制。因为初步工作表明神经酰胺
激活蛋白磷酸酶,目标包括确定a)
2D研究神经酰胺对内源蛋白质磷酸化的影响
电泳法;b)神经酰胺激活蛋白质的能力
磷酸酶;c)神经酰胺类似物的结构-功能活性
激活磷酸酶和下调c-myc;以及d)
磷酸酶抑制剂对神经酰胺和肿瘤坏死因子-α作用的影响。希望是这样的
这些研究将定义一种新的信号通路,可能揭示
重要的治疗靶点,调节细胞增殖和
差异化。
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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Robert Wolff其他文献
Robert Wolff的其他文献
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{{ truncateString('Robert Wolff', 18)}}的其他基金
The UT MD Anderson Cancer Center Community Clinical Oncology Program Research Bas
UT MD 安德森癌症中心社区临床肿瘤学项目研究基地
- 批准号:
8528341 - 财政年份:1996
- 资助金额:
$ 7.73万 - 项目类别:
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