MACROPHAGE RESPONSES TO BACTERIAL TOXINS
巨噬细胞对细菌毒素的反应
基本信息
- 批准号:2887354
- 负责人:
- 金额:$ 0.29万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1997
- 资助国家:美国
- 起止时间:1997-07-01 至 1999-07-31
- 项目状态:已结题
- 来源:
- 关键词:Bacillus bacterial toxins biological signal transduction combinatorial chemistry cytokine endopeptidases enzyme activity free radical oxygen genetic library immunoregulation inflammation macrophage molecular cloning nuclear factor kappa beta nucleic acid sequence phagocytes receptor binding receptor expression toxin metabolism tumor necrosis factor alpha
项目摘要
DESCRIPTION (Adapted from the applicant's abstract): The proposed studies
will examine the causes of misregulation of macrophage inflammatory
responses. Pathogen-phagocytes interactions are critical in many infectious
diseases. A newly recognized bacterial pathogen strategy is the expression
of toxins which upregulate inflammatory functions which directly mediate
acute pathologies and symptoms. Hyperstimulation of important macrophage
functions by toxin was first described using the anthrax system. Anthrax
lethal toxin mimics all the symptoms of systemic anthrax including death.
Upon entering the macrophage, the toxin induces an extreme oxidative burst
producing oxygen radicals (ROI) which rupture cell membranes. Lethal toxin
also induces overexpression of TNF_ and IL-1_ which directly cause symptoms
and death in BALB/c mice. Macrophage-depleted mice are toxin-resistant.
This well-defined model will be used to uncover patterns of key regulatory
points of the lethal inflammatory process. The first goal is to identify
macrophage target proteins for the lethal toxin protease activity using
combinatorial chemistry techniques and to understand their role in mediating
inflammation. The second major aim is to elucidate the role of the anthrax
toxin receptor in this process. It is proposed to clone the receptor gene
from _gt11 macrophage cDNA libraries and to determine sequence, receptor
number and natural functions. The third aim will examine the signaling
relationship between ROIs and initiation of immuno-specific macrophage gene
expression. NF_B will be examined as a signaling element inking the two
events. It is becoming apparent that highly targeted disruption of the
normal regulation of immune cell antimicrobial functions by bacterial
factors induce overexpression of host mediators of septic shock, acute
respiratory distress syndrome and other pathologies seen during infections.
Activation of the same systems contribute to autoimmune and chronic
inflammatory disorders. This proposal examines key molecular aspects of
these regulated pathways.
描述(改编自申请人的摘要):建议的研究
将研究巨噬细胞炎症调节失调的原因
回应。病原体-吞噬细胞的相互作用在许多感染性疾病中是至关重要的
疾病。一种新发现的细菌病原体策略是表达
毒素可上调炎症功能,从而直接介导
急性病理和症状。重要巨噬细胞的过度刺激
毒素的功能首先是使用炭疽系统描述的。炭疽病
致命毒素模仿系统性炭疽热的所有症状,包括死亡。
一旦进入巨噬细胞,毒素就会引起极端的氧化爆发。
产生氧自由基(ROI),使细胞膜破裂。致命毒素
还可诱导直接引起症状的肿瘤坏死因子α和白介素1α的过度表达
和BALB/c小鼠死亡。巨噬细胞耗尽的小鼠对毒素具有抵抗力。
这一定义明确的模型将用于揭示关键监管模式
致命性炎症过程的要点。第一个目标是确定
利用巨噬细胞靶蛋白对致死毒素蛋白水解酶的活性
组合化学技术及其在调节中的作用
发炎。第二个主要目的是阐明炭疽病的作用。
毒素受体参与了这一过程。有人建议克隆受体基因。
从_gt11巨噬细胞c DNA文库中克隆并测定序列、受体
数和自然函数。第三个目标将检查信号
ROI与免疫特异性巨噬细胞基因启动的关系
表情。核因子B将被视为连接两者的信号元件
事件。越来越明显的是,高度有针对性的破坏
细菌对免疫细胞抗菌功能的正常调节
急性感染性休克宿主介质诱导因子的过度表达
在感染期间出现的呼吸窘迫综合征和其他病理。
相同系统的激活有助于自身免疫和慢性
炎症性疾病。这项提案研究了关键的分子方面的
这些受调控的通路。
项目成果
期刊论文数量(0)
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会议论文数量(0)
专利数量(0)
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{{ truncateString('Philip C Hanna', 18)}}的其他基金
FORMATION/COMPOSITION: BACILLUS ANTHRACIS ENDOSPORE
组成/成分:炭疽杆菌内孢子
- 批准号:
6979700 - 财政年份:2004
- 资助金额:
$ 0.29万 - 项目类别:
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