ALCOHOL EFFECT OF AZT PHOSPHORYLATION REQUIRED FOR ACTIVATION OF AZT
AZT 激活所需的 AZT 磷酸化的醇效应
基本信息
- 批准号:6345865
- 负责人:
- 金额:$ 18.46万
- 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:1999-12-01 至 2000-11-30
- 项目状态:已结题
- 来源:
- 关键词:HIV infections RNA biosynthesis alcoholic beverage consumption autoradiography bone marrow colony stimulating factor cytotoxicity enzyme activity ethanol genetically modified animals hematopoietic stem cells immunosuppression laboratory mouse liver messenger RNA northern blottings phosphorylation thymidine kinase thymidylate kinase thymus zidovudine
项目摘要
3'-Azido-2',3'-dideoxythymidine (AZT), the chemotherapeutic agent of first
choice for patients with HIV disease, requires cellular activation
catalyzed by a series of cellular kinases to the triphosphate form (AZT-
TP) for antiviral activity. Two rate-limiting steps in the cascade of
activation have been identified: 1) thymidine kinase, the enzyme that
converts AZT to its monophosphate (AZT-MP), and 2) thymidylate kinase, the
enzyme that converts AZT to its diphosphate (AZT-DP). Earlier studies have
shown that the antiviral activity of AZT can be reduced through defect in
the expression of any one of these kinases. In addition, AZT therapy is
regularly accompanied by severe hematopoietic toxicity leading to anemia
and leukopenia. Currently, there is no information on how alcohol
consumption might alter the conversion of AZT to its active form or modify
the toxic effects of the drug in HIV-1 affected individuals. There is
evidence that alcohol has the ability to down-regulate the expression of
thymidine kinase as well as impair the growth of hematopoietic progenitors
in culture. It is our hypothesis that alcohol in the presence of HIV-1
protein(s) will 1) down-regulate the expression of thymidine-thymidylate
kinases and inhibit the activation of AZT to its active form; and 2)
enhance toxic effects of AZT on hematopoietic progenitor cells. This
proposal will test the hypothesis in transgenic mice that express full-
length Tat (Tat/86) protein, and in mice (HIV mice) that express a number
of HIV-encoded proteins, and has 6 Specific Aims. Specific Aim 1, to test
the prediction that alcohol suppresses activities of thymidine-thymidylate
kinases in bone marrow, thymus and liver tissues of mice. Since AZT is
known to diminish its own phosphorylation, in Specific Aim 2, we will
assess the effects of alcohol in AZT-treated mice. In order to test the
prediction that suppression of thymidine-thymidylate kinases is linked to
decreased AZT phosphorylation. In Specific Aim 3, we will measure the
capacity of the mouse tissues to phosphorylate AZT in in vitro assays. In
Specific Aim 4, we will test the prediction that the suppression of
thymidine kinase activity seen in Aims 1 and 2 is the result of comparable
decreases in its mRNA synthesis. In Specific Aims 5 and 6, we will test
the prediction that alcohol consumption has suppressive effect on the
proliferation of bone marrow progenitors and further enhances the
suppressive effects of AZT. The results of the proposed studied will
provide new insights into the co-factor role of alcohol in HIV
pathogenesis through decreased antiviral activity and increased
hematopoietic toxicity of AZT and related drugs.
3 '-叠氮基-2',3 '-双脱氧胸苷(AZT),第一个实施方案的化疗剂,
艾滋病患者的选择,需要细胞活化
由一系列细胞激酶催化为三磷酸形式(AZT-
TP)的抗病毒活性。级联反应中的两个限速步骤
已经鉴定了以下激活:1)胸苷激酶,
将AZT转化为单磷酸(AZT-MP),和2)胸苷酸激酶,
将AZT转化为二磷酸盐(AZT-DP)的酶。早期的研究
显示AZT的抗病毒活性可以通过缺陷而降低,
任何一种激酶的表达。此外,AZT治疗是
经常伴有严重的造血毒性,导致贫血
和白细胞减少症。目前还没有关于酒精如何
服用AZT可能会改变AZT向其活性形式的转化,
该药物对HIV-1感染者的毒性作用。有
有证据表明酒精能够下调
胸苷激酶以及损害造血祖细胞的生长
在文化中。我们的假设是,在HIV-1存在的情况下,
蛋白质将1)下调胸苷-胸苷酸的表达
激酶并抑制AZT活化成其活性形式;和2)
增强AZT对造血祖细胞的毒性作用。这
这项提案将在表达完整基因的转基因小鼠中检验这一假设,
长度达特(达特/86)蛋白,并且在小鼠(HIV小鼠)中表达大量
HIV编码的蛋白质,并有6个特定的目的。具体目标1,测试
酒精抑制胸苷酸活性预测
小鼠骨髓、胸腺和肝组织中的激酶。由于AZT是
众所周知,它会减少自身的磷酸化作用,在具体目标2中,我们将
评估酒精对AZT治疗小鼠的影响。为了测试
预测抑制胸苷-胸苷酸激酶与
降低AZT磷酸化。在具体目标3中,我们将测量
体外试验中小鼠组织磷酸化AZT的能力。在
具体目标4,我们将测试的预测,抑制
目的1和2中观察到的胸苷激酶活性是可比较的
减少mRNA的合成。在具体目标5和6中,我们将测试
预测酒精消费对
增殖的骨髓祖细胞,并进一步增强
AZT的抑制作用拟议研究的结果将
为酒精在艾滋病毒中的辅助因素作用提供了新的见解
通过降低抗病毒活性和增加
AZT及相关药物的造血毒性。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('OM PRAKASH', 18)}}的其他基金
ACQUISITION OF A 500MHZ HIGH-RESOLUTION NMR CRYOPROBE
采集 500MHZ 高分辨率 NMR 冷冻探针
- 批准号:
7335135 - 财政年份:2006
- 资助金额:
$ 18.46万 - 项目类别:
ALCOHOL EFFECT OF AZT PHOSPHORYLATION REQUIRED FOR ACTIVATION OF AZT
AZT 激活所需的 AZT 磷酸化的醇效应
- 批准号:
6652164 - 财政年份:2002
- 资助金额:
$ 18.46万 - 项目类别:
ALCOHOL EFFECT OF AZT PHOSPHORYLATION REQUIRED FOR ACTIVATION OF AZT
AZT 激活所需的 AZT 磷酸化的醇效应
- 批准号:
6563176 - 财政年份:2001
- 资助金额:
$ 18.46万 - 项目类别:
ALCOHOL EFFECT OF AZT PHOSPHORYLATION REQUIRED FOR ACTIVATION OF AZT
AZT 激活所需的 AZT 磷酸化的醇效应
- 批准号:
6409984 - 财政年份:2000
- 资助金额:
$ 18.46万 - 项目类别:
ALCOHOL EFFECT OF AZT PHOSPHORYLATION REQUIRED FOR ACTIVATION OF AZT
AZT 激活所需的 AZT 磷酸化的醇效应
- 批准号:
6218632 - 财政年份:1999
- 资助金额:
$ 18.46万 - 项目类别:
ALCOHOL EFFECT OF AZT PHOSPHORYLATION REQUIRED FOR ACTIVATION OF AZT
AZT 激活所需的 AZT 磷酸化的醇效应
- 批准号:
6097709 - 财政年份:1999
- 资助金额:
$ 18.46万 - 项目类别:
ALCOHOL EFFECT OF AZT PHOSPHORYLATION REQUIRED FOR ACTIVATION OF AZT
AZT 激活所需的 AZT 磷酸化的醇效应
- 批准号:
6299182 - 财政年份:1999
- 资助金额:
$ 18.46万 - 项目类别:
MOLECULAR DETERMINANTS OF HIV EXPRESSION BY OPIATES
阿片类药物表达 HIV 的分子决定因素
- 批准号:
3213117 - 财政年份:1989
- 资助金额:
$ 18.46万 - 项目类别: