MACROPHAGE RESPONSES TO BACTERIAL TOXINS

巨噬细胞对细菌毒素的反应

• 批准号: 2404076
• 负责人: Philip C Hanna
• 金额: $ 19.69万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2404076
• 关键词: Bacillus; bacterial toxins; biological signal transduction; 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

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（改编自申请人摘要）：拟定研究 将研究巨噬细胞炎症调节失调的原因， 应答 病原体-吞噬细胞相互作用在许多感染性疾病中是至关重要的。 疾病 一种新认识的细菌病原体策略是表达 这些毒素能上调炎症功能， 急性病理和症状。 重要巨噬细胞过度刺激 毒素的功能首先是使用炭疽系统描述的。 炭疽 致命毒素模仿炭疽病的所有症状包括死亡。 一旦进入巨噬细胞，毒素会引发极端的氧化爆发 产生氧自由基（ROI），其使细胞膜破裂。 致死毒素 还诱导TNF_和IL-1_的过度表达，直接引起症状 BALB/c小鼠死亡。 巨噬细胞耗尽的小鼠对毒素有抵抗力。 这个定义明确的模型将用于揭示关键监管模式， 致命的炎症过程。 第一个目标是确定 巨噬细胞靶蛋白的致死毒素蛋白酶活性， 组合化学技术，并了解它们在介导 炎症 第二个主要目的是阐明炭疽的作用 毒素受体在这个过程中。 建议克隆受体基因 从_gt11巨噬细胞cDNA文库，并确定序列，受体 自然数与自然函数 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 NF_B将被作为一个信令元素来检查， 事件 越来越明显的是， 细菌对免疫细胞抗菌功能的正常调节 因子诱导感染性休克、急性 呼吸窘迫综合征和其他感染过程中出现的病理。 相同系统的激活有助于自身免疫性和慢性 炎症性疾病 该提案审查了以下关键分子方面： 这些受调控的途径。