CYTOSTATIC ROLE OF THE ARGININE-NITRIC OXIDE PATHWAY
CYTOSTATIC ROLE OF THE ARGININE-NITRIC OXIDE PATHWAY
批准号:
2842312
负责人:
LOUIS J IGNARRO
金额:
$28.47万
依托单位国家:
美国
项目类别:
财政年份:
1999
资助国家:
美国
项目状态:
已结题
起止时间:
1999-04-01 至 2002-03-31
中文摘要
一氧化氮(NO)被认为干扰细胞增殖,
尽管其抑制细胞生长的作用机制在很大程度上是未知的。这
这一观点是基于这样的观察,即没有供体试剂或诱导
培养细胞中的NO合酶与伴随的
减弱细胞增殖。我们发现N/G-羟基-L-
精氨酸(NOHA),精氨酸氧化为NO +的中间体
瓜氨酸是在培养的细胞中合成和释放的。NOHA是一个
有效的竞争性抑制剂或抑制剂(Ki = 10 μ M),并关闭
在细胞中产生鸟氨酸+尿素。鸟氨酸是
腐胺和细胞增殖所需的其它多胺。我们有
还发现NO抑制鸟氨酸脱羧酶活性。的
这项研究的主要目的是确定是否没有
合成酶通过NOHA和NO的生物学作用,
或在调节血管光滑生长中的病理生理作用
肌肉细胞和肿瘤细胞,并阐明其机制,
细胞生长受到抑制。推动这一理论的核心假设是
建议是NO合酶反应的两种产物,NOHA和NO,
通过抑制两种细胞增殖,
连续的酶促步骤(NOHA抑制辅酶Ⅱ酶; NO抑制辅酶Ⅱ酶;
鸟氨酸脱羧酶)的途径,导致生产
多胺从精氨酸。这些额外的细胞抑制机制
NO合成酶活性增加的结果将补充其他
已知NO的细胞抑制机制如鸟苷酸环化酶激活
和环GMP介导的DNA合成损伤。的两个具体
为严格检验所提出的假设而采取的目标是:
(a)以确定NOHA、NO和NO合酶
活性干扰生理或生理条件下的细胞增殖
病理生理条件和(B)阐明机制,
NO抑制鸟氨酸脱羧酶。拟议的研究应
推进我们对NO合酶在生物学作用的理解,
调节细胞增殖。
英文摘要
Nitric oxide (NO) is believed to interfere with cell proliferation,
although its mechanism of cytostatic action is largely unknown. This
view is based on the observations that NO donor agents or induction of
NO synthase in cultured cells is associated with the concomitant
attenuation of cell proliferation. We have found that N/G-hydroxy-L-
arginine (NOHA), an intermediate in the oxidation of arginine to NO +
citrulline, is synthesized and released from cells in culture. NOHA is a
potent competitive inhibitor or arginase (Ki = 10 muM) and turns off
production of ornithine + urea in cells. Ornithine is the precursor to
putrescine and other polyamines required for cell proliferation. We have
also found that NO inhibits ornithine decarboxylase activity. The
principal objective of the proposed research is to determine whether NO
synthase, via the biologic actions of NOHA and NO, plays a physiological
or pathophysiological role in regulating the growth of vascular smooth
muscle cells and tumor cells, and to elucidate the mechanisms by which
cell growth is inhibited. The central hypothesis that drives this
proposal is that two products of the NO synthase reaction, NOHA and NO,
function biologically to slow cell proliferation by inhibiting two
sequential enzymatic steps (NOHA inhibits arginase; NO inhibits
ornithine decarboxylase) in the pathway leading to the production of
polyamines from arginine. These additional cytostatic mechanisms
resulting from increased NO synthase activity would complement other
known cytostatic mechanisms of NO such as guanylyl cyclase activation
and cyclic GMP-mediated impairment of DNA synthesis. The two specific
aims that will be taken to rigorously test the proposed hypothesis are:
(a) to ascertain the mechanisms by which NOHA, NO and NO synthase
activity interfere with cell proliferation under physiological or
pathophysiological conditions and (b) to elucidate the mechanism by
which NO inhibits ornithine decarboxylase. The proposed research should
advance our understanding of the biological role of NO synthase in
regulating cell proliferation.
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会议论文
Arginase and Nitric Oxide in Atherosclerosis
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批准号:6697306
-
项目类别:
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资助金额:$34.89万
-
财政年份:2001
-
负责人:LOUIS J IGNARRO
-
依托单位:
Arginase and Nitric Oxide in Atherosclerosis
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批准号:6499182
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项目类别:
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资助金额:$33.29万
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财政年份:2001
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负责人:LOUIS J IGNARRO
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依托单位:
Arginase and Nitric Oxide in Atherosclerosis
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批准号:6629161
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项目类别:
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资助金额:$34.05万
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财政年份:2001
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负责人:LOUIS J IGNARRO
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依托单位:
Arginase and Nitric Oxide in Atherosclerosis
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批准号:6316119
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项目类别:
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资助金额:$42.97万
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财政年份:2001
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负责人:LOUIS J IGNARRO
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依托单位:
CYTOSTATIC ROLE OF THE ARGININE-NITRIC OXIDE PATHWAY
-
批准号:6184223
-
项目类别:
-
资助金额:$29.27万
-
财政年份:1999
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负责人:LOUIS J IGNARRO
-
依托单位:
CYTOSTATIC ROLE OF THE ARGININE-NITRIC OXIDE PATHWAY
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批准号:6389673
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项目类别:
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资助金额:$30.01万
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财政年份:1999
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负责人:LOUIS J IGNARRO
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依托单位:
ENDOTHELIUM IN CARDIOVASCULAR FUNCTION
-
批准号:2031411
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项目类别:
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资助金额:$1.0万
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财政年份:1997
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负责人:LOUIS J IGNARRO
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依托单位:
BIOCHEMISTRY AND MOLECULAR BIOLOGY OF NITRIC OXIDE
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批准号:3435450
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项目类别:
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资助金额:$0.5万
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财政年份:1994
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负责人:LOUIS J IGNARRO
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依托单位:
REGULATION OF EXPRESSION OF NO SYNTHASE
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批准号:2842819
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项目类别:
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资助金额:$29.17万
-
财政年份:1990
-
负责人:LOUIS J IGNARRO
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依托单位:
REGULATION OF ACTIVITY AND EXPRESSION OF NO SYNTHASE
-
批准号:2714008
-
项目类别:
-
资助金额:$33.6万
-
财政年份:1990
-
负责人:LOUIS J IGNARRO
-
依托单位:
REGULATION OF ACTIVITY AND EXPRESSION OF NO SYNTHASE
-
批准号:2219798
-
项目类别:
-
资助金额:$31.4万
-
财政年份:1990
-
负责人:LOUIS J IGNARRO
-
依托单位:
REGULATION OF EXPRESSION OF NO SYNTHASE
-
批准号:6182323
-
项目类别:
-
资助金额:$29.94万
-
财政年份:1990
-
负责人:LOUIS J IGNARRO
-
依托单位:
REGULATION OF ACTIVITY AND EXPRESSION OF NO SYNTHASE
-
批准号:2219796
-
项目类别:
-
资助金额:$30.36万
-
财政年份:1990
-
负责人:LOUIS J IGNARRO
-
依托单位:
PHARMACODYNAMICS OF ENDOTHELIUM-DERIVED NITRIC OXIDE
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批准号:3358283
-
项目类别:
-
资助金额:$29.13万
-
财政年份:1990
-
负责人:LOUIS J IGNARRO
-
依托单位:
PHARMACODYNAMICS OF ENDOTHELIUM-DERIVED NITRIC OXIDE
-
批准号:3358284
-
项目类别:
-
资助金额:$30.46万
-
财政年份:1990
-
负责人:LOUIS J IGNARRO
-
依托单位:
REGULATION OF ACTIVITY AND EXPRESSION OF NO SYNTHASE
-
批准号:2430672
-
项目类别:
-
资助金额:$32.47万
-
财政年份:1990
-
负责人:LOUIS J IGNARRO
-
依托单位:
REGULATION OF EXPRESSION OF NO SYNTHASE
-
批准号:6389067
-
项目类别:
-
资助金额:$30.71万
-
财政年份:1990
-
负责人:LOUIS J IGNARRO
-
依托单位:
REGULATION OF EXPRESSION OF NO SYNTHASE
-
批准号:6526702
-
项目类别:
-
资助金额:$31.49万
-
财政年份:1990
-
负责人:LOUIS J IGNARRO
-
依托单位:
PHARMACODYNAMICS OF ENDOTHELIUM-DERIVED NITRIC OXIDE
-
批准号:2219795
-
项目类别:
-
资助金额:$34.17万
-
财政年份:1990
-
负责人:LOUIS J IGNARRO
-
依托单位:
PHARMACODYNAMICS OF ENDOTHELIUM-DERIVED NITRIC OXIDE
-
批准号:3358286
-
项目类别:
-
资助金额:$32.78万
-
财政年份:1990
-
负责人:LOUIS J IGNARRO
-
依托单位:
海外基金