PATHOGENESIS OF FEVER IN HUMANS

人类发烧的发病机制

• 批准号: 2404924
• 负责人: Charles anthony Dinarello
• 金额: $ 44.73万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-12-01 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2404924
• 关键词: T lymphocyte; acute phase protein; binding proteins; body temperature regulation; cell type; chemical structure function; colchicine; endotoxins; gel electrophoresis; gel filtration chromatography; gene expression; genetic transcription; genetic translation; hemodialysis; human tissue; hyperthermia; immunofluorescence technique; interleukin 1; ion exchange chromatography; laboratory mouse; laboratory rabbit; lipoxygenase; marine animal oil; monoclonal antibody; monocyte; protein biosynthesis; protein sequence; pyrogens; radioimmunoassay; radiotracer; synthetic peptide; tissue /cell culture; toxic shock syndrome; tumor necrosis factor alpha

This proposal concerns interleukin-1 (IL-1) as a key mediator of host responses to microbial invasion, inflammation, immunological reaction and injury. IL-1 is one of the first and most prominent molecular synthesized following the onset of infection or injury. Many of IL-1's effects are involved with pathological processes, and the host has mechanisms by which synthesis, processing, transport and activities of IL-1 are regulated. This proposal studies these various mechanisms. The experiments are designed to explore IL-1 production from human blood monocytes. Up to 5% of the total polyadenylated RNA codes for IL-1-beta in monocytes after stimulation. Mechanisms control the translation of this RNA into IL-1 protein whereas other mechanisms seem to control processing of the primary translation product into biologically active IL-1. Transcription, translation and processing of IL-1 are different in blood monocytes than in cultured cells lines. Therefore, these experiments are focused on each of the steps of IL-1 production in circulating human blood cells in health, in disease and under the influence of various disease modifying substances. special methods will be employed that prevent the transcription of Il-1 in monocytes due to adherence to surfaces. Two newly developed radioimmunoassays for IL-1-beta and Il-1- alpha will be used in a large study to establish what constitutes "normal" Il-1 production. Immunoprecipitation and immunofluorescence using specific, non-cross reacting antibodies will be used to detect the sizes and cellular localization of IL-1. The specific biological activities of Il-1 differ with the molecular size and hence studies on the structure-function relationship of IL-1 are proposed in order to identify a putative active site(s). The evaluation of synthetic peptides will be performed and correlated with naturally occurring fragments of monocyte Il-1. An animal model of hemodynamic shock using toxic shock syndrome toxin is to be used to evaluate the systemic effects of Il-1, its fragments and substances that inhibit its biological activities. Two clinical models will be used to study Il-1 production in human subjects: the effect of supplemental fish oil diet and hemodialysis. These studies complement the basic investigations on the molecular control of IL-1 production. Finally, these studies examine the production and activity of IL-1 in models of endogenous amplification and inhibition.

这项提议涉及到白介素1(IL-1)作为一种关键的 宿主对微生物入侵、炎症、免疫的反应 反应和损伤。IL-1是最早也是最突出的 在感染或损伤发生后合成的分子。 IL-1的S效应有很多与病理过程有关， 并且宿主具有合成、加工、 IL-1的转运和活性受到调控。这项建议 研究了这些不同的机制。实验是设计的 目的：探讨人血单核细胞产生IL-1的能力。至.为止 IL-1-β的总多聚腺苷RNA编码的5% 刺激后的单核细胞。机制控制着翻译 将这种RNA转化为IL-1蛋白，而其他机制似乎 控制将主要翻译产品处理为 具有生物活性的IL-1。转录、翻译和加工 IL-1在血液单核细胞中的表达与培养细胞中的不同 台词。因此，这些实验的重点是每一个 健康人体血液循环中产生IL-1的步骤， 在疾病中和在各种疾病修改的影响下 物质。将采用特殊方法防止 单核细胞表面黏附对IL-1转录的影响 两种新发展的IL-1-β和IL-1放射免疫分析方法 阿尔法将用于一项大型研究，以确定构成 “正常”的伊尔-1生产。免疫沉淀和 使用特异性、非交叉反应抗体的免疫荧光 将用于检测IL-1的大小和细胞定位。 IL-1的特定生物学活性与分子水平不同。 大小和结构-功能关系的研究 IL-1的提出是为了确定一个可能的活性部位(S)。 将对合成肽进行评估，并 与自然产生的单核细胞IL-1片段相关。 利用中毒性休克建立血流动力学休克动物模型 证候毒素可用来评价丹参的全身效应 IL-1及其片段和抑制其生物学活性的物质 活动。将使用两个临床模型来研究IL-1 补充鱼油对人体生殖功能的影响 饮食和血液透析。这些研究补充了基本的 IL-1产生的分子调控研究。 最后，这些研究检查了IL-1的产生和活性 在内源性放大和抑制模型中。