CD14 AND OTHER LPS RECEPTORS AND ENDOTOXIN SHOCK

CD14 和其他 LPS 受体与内毒素休克

• 批准号: 2671871
• 负责人: Sanna M Goyert
• 金额: $ 40.99万
• 依托单位: NORTH SHORE UNIVERSITY HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-01-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2671871
• 关键词: CD antigens; antigen receptors; antireceptor antibody; disease /disorder model; endotoxins; gene expression; genetic manipulation; gram negative bacteria; gram positive bacteria; laboratory mouse; lipopolysaccharides; microorganism immunology; molecular pathology; protein structure; septic shock; tissue /cell culture

DESCRIPTION (Adapted from applicant's abstract): The ability to reproduce endotoxin shock in mice provides a unique opportunity to study the biology of the disease and its consequences. The studies proposed here take advantage of the ease of doing experiments in mice and the newest genetic technology. Dr. Goyert has recently produced mice in which the CD14 gene has been disrupted by homologous recombination. These mice provide a unique opportunity to ask several fundamental questions about the nature of endotoxin shock, particularly as regards CD14- dependent and CD14-independent pathways to endotoxin shock. In addition, this animal model will allow Dr. Goyert to evaluate the relative contribution of endothelial cell responses to sCD14- LPS complexes in endotoxin shock.This is the first time that such a model has been established for delineating the effects of these three mechanisms. She will also continue development of a new animal model that will respond to endotoxin in a CD14-dependent manner through the human CD14 protein. This model will be used to evaluate the efficacy of reagents (anti-human CD14 mAb, recombinant soluble human CD14) on the endotoxin response of mice expressing a human CD14 gene and lacking expression of the murine CD14 gene. The following questions will be addressed: 1. How does the lack of CD14 affect the response of CD14-knockout mice to LPS, Gram-negative bacteria, Gram-positive bacteria, and complexes of LPS and soluble CD14? 2. How effective are soluble human CD14 and anti-human CD14 mAb in preventing endotoxin shock in mice expressing human but not murine CD14? Furthermore, can efficacious, unique CD14-specific mAbs be generated in CD14-deficient mice? 3. What is the three-dimensional structure of CD14? 4. What is the nature of the endothelial cell receptor for the complex of LPS-soluble CD14 and is it present on other cell types that also respond to this complex?

描述（改编自申请人的摘要）：复制的能力 小鼠内毒素休克为研究内毒素休克提供了独特的机会 该疾病的生物学及其后果。 这里提出的研究 利用小鼠实验的便利性和最新的 基因技术。 戈耶特博士最近培育出了小鼠，其中 CD14 基因已被同源重组破坏。 这些老鼠 提供了一个独特的机会来提出一些基本问题 内毒素休克的性质，特别是 CD14 依赖性的 和CD14独立的内毒素休克途径。 此外，这 动物模型将使 Goyert 博士能够评估相对贡献 内毒素中内皮细胞对 sCD14-LPS 复合物的反应 震惊。这是第一次建立这样的模型 描述这三种机制的影响。 她还将继续开发一种新的动物模型，该模型将 通过人类 CD14 以 CD14 依赖性方式响应内毒素 蛋白质。 该模型将用于评估试剂的功效 （抗人CD14单克隆抗体，重组可溶性人CD14）对内毒素的影响 表达人类 CD14 基因但缺乏表达的小鼠的反应 鼠CD14基因。 将解决以下问题： 1. 缺少CD14怎么办？ 影响 CD14 敲除小鼠对 LPS、革兰氏阴性菌的反应， 革兰氏阳性菌、LPS 和可溶性 CD14 的复合物？ 2. 如何 可溶性人 CD14 和抗人 CD14 mAb 可以有效预防 表达人类但不表达鼠 CD14 的小鼠发生内毒素休克？ 此外，可以在中产生有效的、独特的CD14特异性mAb吗？ CD14缺陷小鼠？ 3. CD14的三维结构是什么？ 4. 该复合物的内皮细胞受体的性质是什么 LPS 可溶性 CD14 是否也存在于其他细胞类型上 对这个复杂的反应？