CD14 AND OTHER LPS RECEPTORS AND ENDOTOXIN SHOCK

描述（改编自申请人摘要）：复制能力 小鼠内毒素休克提供了研究 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， 基因技术 戈耶特博士最近制造了一种小鼠， 通过同源重组破坏了CD 14基因。 这些小鼠 提供了一个独特的机会，问几个基本问题， 内毒素休克的性质，特别是关于CD 14依赖性 和CD 14-非依赖性途径导致内毒素休克。 另外这款 动物模型将允许Goyert博士评估相对贡献 内皮细胞对sCD 14- LPS复合物的反应 冲击。这是第一次建立这样的模型， 描述这三种机制的作用。 她还将继续开发新的动物模型， 通过人CD 14以CD 14依赖性方式应答内毒素 蛋白 该模型将用于评价试剂的有效性 （抗人CD 14 mAb，重组可溶性人CD 14）对内毒素的影响 表达人CD 14基因和缺乏人CD 14基因表达的小鼠的免疫应答 鼠CD 14基因。 以下问题将得到解决：1。缺乏CD 14是如何 影响CD 14基因敲除小鼠对LPS、革兰氏阴性菌 革兰氏阳性菌，LPS和可溶性CD 14？ 2. 如何 可溶性人CD 14和抗人CD 14 mAb在预防 内毒素休克小鼠表达人，但不鼠CD 14？ 此外，是否可以在小鼠中产生有效的、独特的CD 14特异性mAb， CD 14缺陷小鼠？ 3. CD 14的三维结构是什么？ 4.复合物的内皮细胞受体的性质是什么 LPS可溶性CD 14的表达，它是否存在于其他细胞类型上， 回应这种复杂？

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?