SMOKELESS TOBACCO--MECHANISMS OF BUCCAL MUCOSA INJURY
无烟烟草——颊粘膜损伤的机制
基本信息
- 批准号:2128831
- 负责人:
- 金额:$ 6.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1994
- 资助国家:美国
- 起止时间:1994-04-01 至 1998-11-30
- 项目状态:已结题
- 来源:
- 关键词:DNA replication bradykinin cell cycle cellular pathology cheek pouch technique drug interactions drug metabolism drug related neoplasm /cancer endopeptidases enzyme activity epithelium gene expression genetic regulation hamsters inflammation messenger RNA metalloenzyme molecular pathology neuropeptide receptor oncogenes oral mucosa peptidyl dipeptidase A smokeless tobacco tissue /cell culture vascular endothelium permeability
项目摘要
The use of smokeless tobacco (ST) in increasing in the United States.
Recent epidemiological and clinical evidence suggests that regular use
of ST is associated with buccal mucosa injury, inflammation and
epithelial cell dysplasia. However, the mechanisms that mediate these
effects are still poorly understood. The basic tenet of this proposal
is that ST induces buccal mucosa injury, inflammation and epithelial cell
proliferation, in part, by altering local kinin metabolism. We
hypothesized that exposure of the buccal mucosa to ST is associated with:
1) local generation and release of bradykinin (BK) that has potent
inflammatory and mitogenic effects; 2) decreased activity and/or
expression of the membrane-bound metalloenzymes angiotensin-converting
enzymes (ACE; EC 3.4.15.1) and neutral endopeptidase (NEP; EC 23.4.24.11)
that are widely distributed in the buccal mucosa and degrade BK very
effectively; 3) potentiation of BK-induced buccal mucosa epithelial cell
proliferation; and 4) upregulation Ki-ras oncongene expression in buccal
mucosa epithelial cells leading upregulation of BK receptors in these
cells. The net result would be a decrease in BK catabolism in the buccal
mucosa combined with and increase in the number and/or affinity of its
receptors in epithelial cells leading to potentiation of BK-induced plasm
extravasation and epithelial cell proliferation. In the present
proposal, we will use the hamster cheek pouch to investigate the
following specific aims: 1) to determine whether ST increases vascular
permeability in the hamster check pouch, and whether these effects are
modulated by ACE and NEP; 2) to investigate whether ST induces BK
generation and release in the hamster cheek pouch; 3) to determine
whether ST decreases the activity and expression of ACE and NEP in the
hamster cheek pouch; 4) to investigate whether ST interacts with BK to
induce hamster cheek pouch epithelial cell DNA synthesis and
proliferation in vitro, and whether these effects are modulated by ACE
and NEP; and 5) to determine whether ST upregulates BK receptors in
cultured hamster cheek pouch epithelial cells, and whether these effects
are associated with increased expression of Ki-ras mRNA. The results of
the proposed studies will provide new insights into mechanisms that may
mediate the injurious effects of ST in the buccal mucosa. In the long
term, they may also provide a rationale for the development of novel
strategies to treat oral lesions associated with the regular use of ST
in human subjects.
无烟烟草(ST)的使用在美国不断增加。
最近的流行病学和临床证据表明,经常使用
ST的发生与颊粘膜损伤、炎症和
上皮细胞异型增生。然而,调解这些问题的机制
人们仍然对其影响知之甚少。这项建议的基本原则是
是ST引起颊粘膜损伤、炎症和上皮细胞
增殖,部分是通过改变局部激动素代谢来实现的。我们
假设口腔粘膜暴露于ST与以下因素有关:
1)局部产生和释放缓激肽(BK),具有强大的
炎症和促有丝分裂作用;2)活性降低和/或
膜结合金属酶血管紧张素转换酶的表达
酶(ACE;EC 3.4.15.1)和中性内肽酶(NEP;EC 23.4.24.11)
广泛分布在口腔粘膜中,对BK有很强的降解作用
有效;3)BK对颊粘膜上皮细胞的增强作用
4)颊粘膜Ki-ras癌基因表达上调
粘膜上皮细胞诱导BK受体表达上调
细胞。最终结果将是口腔中BK分解代谢的减少
粘膜结合并增加其数量和/或亲和力
上皮细胞中的受体导致BK诱导的血浆增强
渗出和上皮细胞增殖。在现在
建议,我们将使用仓鼠颊袋来调查
具体目标如下:1)确定ST是否增加血管
在仓鼠检查袋中的渗透性,以及这些影响是否
受ACE和NEP的调控;2)研究ST是否诱导BK
在仓鼠颊囊中产生和释放;3)测定
丹参是否降低大鼠脑内血管紧张素转换酶和神经递质的活性及表达
仓鼠颊囊;4)调查ST是否与BK相互作用
诱导地鼠颊囊上皮细胞DNA合成和
体外增殖以及血管紧张素转换酶是否调节这些效应
和NEP;以及5)确定ST是否上调BK受体。
培养仓鼠颊囊上皮细胞,以及这些影响
与Ki-ras基因表达增加有关。结果是
拟议的研究将为以下机制提供新的见解:
介导ST对颊粘膜的损伤作用。在漫长的岁月里
这也为小说的发展提供了理论基础。
与常规应用ST相关的口腔病变的治疗策略
在人类实验对象中。
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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Micellar VIP Nanoparticles for Rheumatoid Arthritis
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- 批准号:
7076220 - 财政年份:2004
- 资助金额:
$ 6.63万 - 项目类别:
Micellar VIP Nanoparticles for Rheumatoid Arthritis
胶束 VIP 纳米颗粒治疗类风湿关节炎
- 批准号:
6794264 - 财政年份:2004
- 资助金额:
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Micellar VIP Nanoparticles for Rheumatoid Arthritis
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- 批准号:
6931961 - 财政年份:2004
- 资助金额:
$ 6.63万 - 项目类别:
Micellar VIP Nanoparticles for Rheumatoid Arthritis
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- 批准号:
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$ 6.63万 - 项目类别:
SMOKELESS TOBACCO--MECHANISMS OF BUCCAL MUCOSA INJURY
无烟烟草——颊粘膜损伤的机制
- 批准号:
2683933 - 财政年份:1994
- 资助金额:
$ 6.63万 - 项目类别:
SMOKELESS TOBACCO--MECHANISMS OF BUCCAL MUCOSA INJURY
无烟烟草——颊粘膜损伤的机制
- 批准号:
2128832 - 财政年份:1994
- 资助金额:
$ 6.63万 - 项目类别:
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