CD14 AND OTHER LPS RECEPTORS AND ENDOTOXIN SHOCK

描述(改编自申请人的摘要)：繁殖能力 小鼠内毒素休克为研究内毒素休克提供了难得的机会 疾病及其后果的生物学。在这里提出的研究 利用在老鼠身上进行实验的简便性和最新的 基因技术。戈耶特博士最近培育了一些老鼠，在这些老鼠中， CD14基因被同源重组打乱。这些老鼠 提供了一个独特的机会来询问以下几个基本问题 内毒素休克的性质，特别是CD14依赖的休克 以及内毒素休克的CD14非依赖性途径。此外，这一点 动物模型将允许Goyert博士评估相对贡献 内皮细胞对内毒素中sCD14-内毒素复合体的反应 令人震惊。这是第一次为 勾勒出这三种机制的效果。 她还将继续开发一种新的动物模型，这种模型将 通过人CD14以CD14依赖的方式应答内毒素 蛋白。该模型将被用于评估试剂的有效性。 (抗人CD14单抗、重组人可溶性CD14)对内毒素的影响 人CD14基因表达缺失小鼠的免疫应答 小鼠CD14基因。 将解决以下问题：1.CD14的缺乏是如何 影响CD14基因敲除小鼠对内毒素、革兰氏阴性菌、 革兰氏阳性菌，以及内毒素和可溶性CD14的复合体？2.如何 可溶性人CD14和抗人CD14单抗有效预防 表达人CD14而不表达小鼠CD14的小鼠内毒素休克 此外，有效的、独特的CD14特异性单抗能否在 CD14缺陷小鼠？3.CD14的三维结构是什么？ 4.复合体的内皮细胞受体的性质是什么 以及它是否存在于其他类型的细胞上 对这个情结有什么反应？

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?