INTESTINAL MUSCLE EFFECTS OF CLOSTRIDIUM DIFFICILE TOXIN
INTESTINAL MUSCLE EFFECTS OF CLOSTRIDIUM DIFFICILE TOXIN
批准号:
3454522
负责人:
RICHARD J GILBERT
金额:
$10.74万
依托单位国家:
美国
项目类别:
财政年份:
1989
资助国家:
美国
项目状态:
已结题
起止时间:
1989-07-01 至 1994-03-31
中文摘要
来自艰难梭菌的毒素是主要的
抗生素相关性腹泻的原因。尽管众所周知,许多人
这种和其他感染性腹泻状态的临床表现
都是由于肠肌受累的病理生理学基础
肌肉细胞功能障碍的原因尚不清楚。我们提出了C.
艰难梭菌对肠道平滑肌的直接作用有:1)
B毒素对肌膜电生理及细胞内的影响
钙代谢,2)A毒素通过炎症的间接作用
激活的白细胞释放的介质,以及3)调节
肠神经活动导致神经递质或多肽的变化
放手。这项提案的总体目标是确定
这些现象中的每一种都在肠道对C.
艰难梭菌,并确定其潜在的细胞机制。
首先,由于我们的初步数据表明,毒素B会导致抑制
肠平滑肌钙电导的变化,我们将评估
膜对毒素的电生理反应--兴奋性的研究
大鼠组织条收缩偶联与膜电生理
分离的细胞。毒素B的作用是一个函数的程度
的变化将通过相互关联的变化来研究
酶分散的肌细胞的细胞大小和胞内游离钙,以及
皂苷通透性细胞内钙释放的测定。第二,
毒素对肠神经的影响将直接通过
细胞内膜电生理、突触的测定
对细胞外纤维刺激的反应电位,以及对
肌间神经和粘膜下神经中的外源性激动剂。第三,
因为我们已经证明,体内的毒素A会导致
二十碳二烯和白三烯在体外形成肌膜
去极化,我们将专门研究白三烯C4和
D4在介导离体平滑肌细胞膜兴奋性变化中的作用
细胞和肠神经。
这些研究有望增加我们对细胞
艰难梭菌动力反应的基础,并增强
对传染病病原体作用的一般机制的理解
胃肠道肌肉。
英文摘要
Toxins derived from the bacterium Clostridium difficile are the principal
cause of antibiotic-associated diarrhea. Although it is known that many of
the clinical manifestations of this and other infectious diarrheal states
are due to involvement of intestinal muscle, the pathophysiological basis
of muscle cell dysfunction is unknown. We propose that the effects of C.
difficile on intestinal smooth muscle result from: 1) The direct effects of
toxin B on smooth muscle membrane electrophysiology and intracellular
calcium metabolism, 2) The indirect effect of toxin A via inflammatory
mediators released by activated leukocytes, and 3) The modulation of
enteric nerve activity resulting in changes of neurotransmitter or peptide
release. The overall goal of this proposal is to determine the role of
each of these phenomenon in the motility response of the intestine to C.
difficile, and to ascertain their underlying cellular mechanisms.
First, since our preliminary data suggests that toxin B causes inhibition
of calcium conductance in intestinal smooth muscle, we will evaluate the
membrane electrophysiological response to toxin by studies of excitation-
contraction coupling in tissue strips and membrane electrophysiology in
isolated cells. The degree to which the effects of toxin B are a function
of changes of cystosolic calcium will be studied by correlating changes of
cell size and free cytosolic calcium in enzyme-dispersed muscle cells, and
measurement of calcium release in saponin-permeabilized cells. Second, the
effects of toxins on enteric nerves will be directly studied by
measurements of intracellular membrane electrophysiology, synaptic
potentials in response to extracellular fiber stimulation, and response to
exogenous agonists in myenteric and submucosal nerves in situ. Third,
inasmuch as we have shown that toxin A in vivo results in the release of
eicosanoids and that in vitro leukotriene results in muscle membrane
depolarization, we will specifically study the role of leukotrienes C4 and
D4 in mediating changes of membrane excitability in isolated smooth muscle
cells and enteric nerves.
These studies are expected to increase our understanding of the cellular
basis of the motility response to C. difficile, and to enhance
understanding of the general mechanisms by which infectious agents act on
gastrointestinal muscle.
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会议论文
Lingual Mechanical Function During Swallowing
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批准号:6801077
-
项目类别:
-
资助金额:$28.98万
-
财政年份:2003
-
负责人:RICHARD J GILBERT
-
依托单位:
Lingual Mechanical Function During Swallowing
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批准号:6943985
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项目类别:
-
资助金额:$29.03万
-
财政年份:2003
-
负责人:RICHARD J GILBERT
-
依托单位:
Lingual Mechanical Function During Swallowing
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批准号:6618726
-
项目类别:
-
资助金额:$28.39万
-
财政年份:2003
-
负责人:RICHARD J GILBERT
-
依托单位:
INTESTINAL MUSCLE EFFECTS OF CLOSTRIDIUM DIFFICILE TOXIN
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批准号:3454521
-
项目类别:
-
资助金额:$10.41万
-
财政年份:1989
-
负责人:RICHARD J GILBERT
-
依托单位:
INTESTINAL MUSCLE EFFECTS OF CLOSTRIDIUM DIFFICILE TOXIN
-
批准号:3454519
-
项目类别:
-
资助金额:$2.01万
-
财政年份:1989
-
负责人:RICHARD J GILBERT
-
依托单位:
INTESTINAL MUSCLE EFFECTS OF CLOSTRIDIUM DIFFICILE TOXIN
-
批准号:3454523
-
项目类别:
-
资助金额:$11.17万
-
财政年份:1989
-
负责人:RICHARD J GILBERT
-
依托单位:
INTESTINAL MUSCLE EFFECTS OF CLOSTRIDIUM DIFFICILE TOXIN
-
批准号:3454520
-
项目类别:
-
资助金额:$9.47万
-
财政年份:1989
-
负责人:RICHARD J GILBERT
-
依托单位:
INTESTINAL MUSCLE EFFECTS OF CLOSTRIDIUM DIFFICILE TOXIN
-
批准号:3454524
-
项目类别:
-
资助金额:$7.58万
-
财政年份:1989
-
负责人:RICHARD J GILBERT
-
依托单位:
MUSCARINIC RECEPTOR SUBTYPES IN THE ESOPHAGUS
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批准号:3031344
-
项目类别:
-
资助金额:$3.1万
-
财政年份:1985
-
负责人:RICHARD J GILBERT
-
依托单位:
CLOSTRIDIUM DIFFICILE TOXIN & SMOOTH MUSCLE: CYTOSOLIC CALCIUM/ADENYLATE CYCLASE
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批准号:3931391
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项目类别:
-
资助金额:$0.0万
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财政年份:--
-
负责人:RICHARD J GILBERT
-
依托单位:
CLOSTRIDIUM DIFFICILE TOXIN AND SMOOTH MUSCLE; CALCIUM, ADENYLATE CYCLASE
-
批准号:3910392
-
项目类别:
-
资助金额:$0.0万
-
财政年份:--
-
负责人:RICHARD J GILBERT
-
依托单位:
海外基金