ALCOHOL MODULATION OF RECEPTOR SITES FOR HIV AND PRODUCTION OF CHEMOKINES
HIV 受体位点的酒精调节和趋化因子的产生
基本信息
- 批准号:6652163
- 负责人:
- 金额:$ 13.07万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2002
- 资助国家:美国
- 起止时间:2002-09-01 至 2002-11-30
- 项目状态:已结题
- 来源:
- 关键词:CD4 molecule HIV envelope protein gp120 Kupffer's cell Macaca mulatta Streptococcus pneumoniae alcoholic beverage consumption bacterial pneumonia bactericidal immunity blood chemistry carbohydrate receptor cell membrane chemokine cytokine receptors disease /disorder model ethanol flow cytometry immunosuppression laboratory mouse laboratory rat lipopolysaccharides phagocytosis pharmacokinetics receptor binding receptor expression simian immunodeficiency virus virus receptors virus replication
项目摘要
This proposal is based on the overall hypothesis that alcohol modulates
the hepatic immune system at the plasma membrane and molecular levels by
altering cell surface receptor expression (binding sites for HIV-1) and
production of soluble mediators (chemokines) in hepatic non-parenchymal
cells [NPC], i.e., Kupffer cells and sinusoidal endothelial cells.
Specifically, acute or chronic alcohol regulates the expression of CD4,
chemokine receptors and mannose-specific receptors on hepatic NPC as a
result of ethanol-induced alteration in plasma membranes on hepatic NPC.
This event could also lead to enhanced intracellular production of H2O2
which in turn activates NF-kappaB. The nuclear translocation and
activation of NF-kappaB, a transcription factor, enhances the expression
of m-RNA and synthesis of alpha and beta-chemokines. These chemokines
could potentially block the binding of HIV-1 or exacerbate its replication
in CD4 lymphocytes. The HIV-1 gp120-induced production of beta-chemokines
by hepatic NPC may also be modulated by alcohol. The liver is the major
organ for microbial clearance and ethanol metabolism. Thus, hepatic cells
become susceptible to these agents that could have an impact on the liver
itself as well as on the overall homeostasis of the host. For example
increased production of pro-inflammatory mediators by hepatic NPC which
are the largest contributors of these agents, may also regulate functions
of immunocompetent cells in other organs. Thus, based on these
considerations, the following specific aims are proposed. Specific aim 1:
To determine the effect of acute or chronic alcohol intoxication of hiv-1
GP120 binding, expression of mannose-specific receptors and CD4 on hepatic
NPC. The internalization and degradation of HIV-1 gp120 by hepatic NPC
will be examined. Specific aim 2: To determine the effect of acute or
chronic alcohol intoxication on the intracellular production of H2O2,
activation of NF-kappaB, m-RNA expression and secretion of alpha (CINC or
IL-8) and beta (Rantes, MIP-1 alpha, MIP-1beta, MCP-1) chemokines in
hepatic NPC. The biological activity of HIV-1 gp120 on beta-chemokine
production will be assessed, as well as the role of endogenous and
exogenous endotoxin on the above parameters (specific aims 1&2). The
latter objective will test the hypothesis that chronic alcohol-mediated
influx of LPS from the gut to the circulation is responsible, at least in
part, for the regulation of hepatic NPC functions at the plasma membrane
and molecular levels. Specific aim 3: To determine the effect of chronic
alcohol intoxication on hepatic NPC functions, i.e., superoxide anion
production, phagocytosis, chemokine and cytokine production, chemokine
receptor (CXCR4 & CCR5) expression and SIV gp120 binding. This study will
also examine chemokine-mediated SIV-1 replication in a simian model of
SIV-1/AIDS. The overall regulation of the above processes by alcohol may
further comprise susceptible individuals to HIV-1 infections and
opportunistic pathogens associated with this viral infection.
这一建议是基于酒精调节的总体假设
肝细胞质膜和分子水平的免疫系统
改变细胞表面受体的表达(HIV-1的结合位点)和
肝非实质组织中可溶性介质(趋化因子)的产生
细胞[NPC],即枯否细胞和肝窦内皮细胞。
具体地说,急性或慢性酒精调节CD4的表达,
趋化因子受体和甘露糖特异性受体在肝源性鼻咽癌中的作用
乙醇致肝鼻咽癌细胞质膜改变的结果。
这一事件也可能导致细胞内过氧化氢的产生增加
进而激活核因子-kappaB。核移位和核转移
转录因子核因子-kappaB的激活增强了该基因的表达
M-RNA和α、β趋化因子的合成。这些趋化因子
可能会阻止HIV-1的结合或加剧其复制
在CD4淋巴细胞中。HIV-1gp120诱导的β-趋化因子的产生
肝脏的鼻咽癌也可能受到酒精的调节。肝为本
微生物清除和乙醇代谢的器官。因此,肝细胞
容易受到这些可能对肝脏产生影响的物质的影响
对寄主的整体动态平衡也有影响。例如
肝脏鼻咽癌增加促炎介质的产生
都是这些制剂的最大贡献者,也可能调节功能
其他器官中免疫活性细胞的数量。因此,基于这些
考虑到这一点,现提出以下具体目标。具体目标1:
确定急性或慢性酒精中毒对HIV-1的影响
肝组织gp120结合、甘露糖特异性受体和CD4的表达
全国人大。肝脏鼻咽癌对HIV-1 gp120的内化和降解
将会被检查。具体目标2:确定急性或慢性疾病的影响
慢性酒精中毒对细胞内过氧化氢产生的影响
核因子-kappaB活化、m-RNA表达和α(CINC或CINC)分泌
IL-8)和β(RANTES、MIP-1α、MIP-1β、MCP-1)趋化因子
肝脏鼻咽癌。HIV-1gp120对β-趋化因子的生物学活性
将评估产量,以及内源和
外源性内毒素对上述参数的影响(特异性目标1和2)。这个
后一项目标将检验慢性酒精介导的假设
内毒素从肠道流入循环是起作用的,至少在
部分,用于在质膜上调节肝脏NPC的功能
和分子水平。具体目标3:确定慢性精神分裂症的影响
酒精中毒对肝脏NPC功能的影响,即超氧阴离子
产生、吞噬、趋化因子和细胞因子的产生
受体(CXCR4和CCR5)表达和SIV gp120结合。这项研究将
也检查趋化因子介导的SIV-1在猴模型中的复制
SIV-1/艾滋病。酒精对上述过程的全面调节可
进一步包括感染HIV-1的易感人群和
与病毒感染相关的机会性病原体。
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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ABRAHAM P. BAUTISTA其他文献
ABRAHAM P. BAUTISTA的其他文献
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{{ truncateString('ABRAHAM P. BAUTISTA', 18)}}的其他基金
ALCOHOL MODULATION OF RECEPTOR SITES FOR HIV AND PRODUCTION OF CHEMOKINES
HIV 受体位点的酒精调节和趋化因子的产生
- 批准号:
6563175 - 财政年份:2001
- 资助金额:
$ 13.07万 - 项目类别:
ALCOHOL MODULATION OF RECEPTOR SITES FOR HIV AND PRODUCTION OF CHEMOKINES
HIV 受体位点的酒精调节和趋化因子的产生
- 批准号:
6409983 - 财政年份:2000
- 资助金额:
$ 13.07万 - 项目类别:
ALCOHOL MODULATION OF RECEPTOR SITES FOR HIV AND PRODUCTION OF CHEMOKINES
HIV 受体位点的酒精调节和趋化因子的产生
- 批准号:
6299181 - 财政年份:1999
- 资助金额:
$ 13.07万 - 项目类别:
ALCOHOL MODULATION OF RECEPTOR SITES FOR HIV AND PRODUCTION OF CHEMOKINES
HIV 受体位点的酒精调节和趋化因子的产生
- 批准号:
6345864 - 财政年份:1999
- 资助金额:
$ 13.07万 - 项目类别:
ALCOHOL MODULATION OF RECEPTOR SITES FOR HIV AND PRODUCTION OF CHEMOKINES
HIV 受体位点的酒精调节和趋化因子的产生
- 批准号:
6218631 - 财政年份:1999
- 资助金额:
$ 13.07万 - 项目类别:
ALCOHOL MODULATION OF RECEPTOR SITES FOR HIV AND PRODUCTION OF CHEMOKINES
HIV 受体位点的酒精调节和趋化因子的产生
- 批准号:
6097708 - 财政年份:1999
- 资助金额:
$ 13.07万 - 项目类别:
RESPIRATORY BURST, CYTOKINES AND HIV IN ALCOHOLICS
酗酒者的呼吸爆发、细胞因子和 HIV
- 批准号:
2516830 - 财政年份:1996
- 资助金额:
$ 13.07万 - 项目类别:
MECHANISMS OF HEPATIC INJURY IN CHRONIC ALCOHOLICS
慢性酗酒者肝损伤的机制
- 批准号:
2047122 - 财政年份:1996
- 资助金额:
$ 13.07万 - 项目类别:
MECHANISMS OF HEPATIC INJURY IN CHRONIC ALCOHOLICS
慢性酗酒者肝损伤的机制
- 批准号:
2682988 - 财政年份:1996
- 资助金额:
$ 13.07万 - 项目类别:
MECHANISMS OF HEPATIC INJURY IN CHRONIC ALCOHOLICS
慢性酗酒者肝损伤的机制
- 批准号:
2389914 - 财政年份:1996
- 资助金额:
$ 13.07万 - 项目类别: