Mouse model for sepsis

脓毒症小鼠模型

• 批准号: 6917492
• 负责人: H Shaw Warren
• 金额: $ 35.49万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6917492
• 关键词: animal tissue; bacterial toxins; cell line; clinical research; disease /disorder model; human subject; interleukin 6; laboratory mouse; laboratory rabbit; lipopolysaccharides; macrophage; model design /development; septicemia; species difference; tumor necrosis factor alpha; vascular endothelium

DESCRIPTION (provided by applicant): Mice are one of the most commonly utilized species for the initial study of many infectious diseases, including the study of the host response to bacteria. However, mice are 100 to 100,000- fold more resistant than humans in most biological responses to the effects of bacterial lipopolysaccharide (LPS), and to many other microbial toxins. In the literature, and in our hands, macrophages from the two species are generally similar in their sensitivity to LPS, regardless of source. Our preliminary data indicate that there is a soluble substance in the serum of mice that strongly suppresses the production of IL-6 and TNF from mouse and human macrophages that are stimulated with many pathogen associated molecular pattern molecules (PAMPs). These data raise the possibility that the reason that mice are resistant to LPS and other bacterial toxins is the presence of this factor in their blood. The overall goal of the proposed work is to understand the mechanism(s) by which mice are resistant to LPS. Our first specific aim is to systematically study the sensitivity of macrophages and endothelial cells from different tissue compartments from mice and humans (where possible), as well as in cell lines, in the presence of serum from LPS-resistant animals (eg rodent, baboon) and LPS-sensitive animals (eg human, fetal calf). Our second specific aim is to purify the material from mouse serum that inhibits the production of TNF from mouse macrophages. Our third specific aim is to study the cellular level of signaling that is inhibited. The project has broad significance because most experiments using mouse cells are currently performed using media supplemented with fetal calf serum rather than mouse serum, because the proposed work will further our understanding of sepsis caused by bacterial pathogens, and because the work could eventually lead to better animal models for the study of sepsis.

描述(由申请人提供)： 在许多传染病的初始研究中，小鼠是最常用的物种之一，包括研究宿主对细菌的反应。然而，在大多数生物反应中，小鼠对细菌脂多糖(LPS)的影响和许多其他微生物毒素的抵抗力是人类的100到100,000倍。在文献中和我们手中，这两个物种的巨噬细胞对内毒素的敏感性通常相似，无论来源如何。我们的初步数据表明，小鼠血清中存在一种可溶性物质，它能强烈抑制许多病原体相关分子模式分子(PAMPs)刺激的小鼠和人巨噬细胞产生IL-6和TNF。这些数据提出了一种可能性，即小鼠对内毒素和其他细菌毒素具有抵抗力的原因是它们的血液中存在这种因素。这项拟议工作的总体目标是了解小鼠抵抗内毒素的机制(S)。我们的第一个特定目标是系统地研究来自小鼠和人类不同组织隔室的巨噬细胞和内皮细胞(如果可能)以及在细胞系中，存在内毒素抵抗的动物(例如啮齿动物、狒狒)和内毒素敏感的动物(例如人、胎牛)的血清的敏感性。我们的第二个特定目标是从小鼠血清中提纯抑制小鼠巨噬细胞产生肿瘤坏死因子的物质。我们的第三个具体目标是研究被抑制的信号的细胞水平。该项目具有广泛的意义，因为目前使用小鼠细胞进行的大多数实验都是使用添加胎牛血清而不是小鼠血清的培养液进行的，因为拟议的工作将加深我们对细菌病原体引起的脓毒症的理解，并且因为该工作最终可能导致更好的脓毒症动物模型的研究。