LPS EFFLUX HOST CELLS TO PLASMA LIPOPROTEINS

LPS 流出宿主细胞至血浆脂蛋白

• 批准号: 6632027
• 负责人: RICHARD L. KITCHENS
• 金额: $ 23.4万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6632027
• 关键词: CD antigens; CD14 molecule; binding proteins; biological transport; blood lipoprotein; cytokine; human subject; inflammation; laboratory mouse; lipopolysaccharides; protein structure function; tissue /cell culture; transfection; transport proteins

Description (adapted from applicant's abstract): Bacterial lipopolysaccharides (LPS) are potent immunomodulatory compounds which, during the course of Gram negative infections, probably play a major role in the induction of septic shock. Therefore, a complete understanding of host mechanisms involved in the transport, detoxification, and attenuation of immune modulation by these potent bacterial membrane constituents will be necessary to formulate effective interventional strategies for septic shock. Previous work from several laboratories has shown that LPS released from the surface of Gram negative bacteria appear to have two fates: LPS may bind to leukocytes to initiate an inflammatory responses, or they made bind to plasma lipoproteins which attenuates LPS bioactivity and facilitates clearance. Recent work in Dr. Kitchens' laboratory suggests that there is an additional component in the host response to LPS. LPS may be removed from the surface of leukocytes and complexed with plasma lipoproteins or mixtures of purified high-density lipoproteins (HDL). This phenomenon is referred to as LPS efflux. The induction of acute phase reactants during inflammation may enhance LPS efflux. Finally, LPS efflux may be responsible for down-regulation of the host inflammatory response to LPS. Four specific aims are offered to address the hypothesis that LPS efflux reduces cellular responses to LPS. Specific aim 1: To determine the roles played by cell surface proteins in LPS traffic between cells and lipoproteins. Specific aim 2: To determine the roles played by soluble lipid transfer proteins in LPS efflux and in responses to cells that have acquired LPS. Specific aim 3: To evaluate the relative importance of natural lipoprotein classes from normal and acute phase plasma as acceptors for cell-associated LPS. Specific aim 4: To study the impact of LPS efflux on cellular responses to LPS.

描述（改编自申请人的摘要）：细菌脂多糖 （LPS）是有效的免疫调节化合物，在克过程中 阴性感染，可能在化粪池诱导中起主要作用 震惊。因此，对涉及的宿主机​​制的完全理解 通过这些有效的运输，排毒和免疫调节的衰减 细菌膜成分需要制定有效 败血性休克的介入策略。以前的工作 实验室表明，LPS从革兰氏阴性表面释放 细菌似乎有两个命运：LP可以与白细胞结合以启动 炎症反应，或者它们与血浆脂蛋白结合，该血浆脂蛋白 减弱LPS生物活性并促进清除率。博士的最新工作 厨房的实验室建议主机中还有一个其他组成部分 对LPS的响应。 LP可以从白细胞表面删除和 与血浆脂蛋白或纯化高密度混合物复合 脂蛋白（HDL）。该现象称为LPS外排。诱导 炎症过程中急性相应物的急性反应物可能会增强LPS外排。最后， LPS外排可能导致宿主炎症的下调 对LPS的响应。提出了四个具体目标，以解决以下假设 LPS外排降低了细胞对LPS的反应。 特定目的1：确定细胞表面蛋白在LPS中起起的作用 细胞和脂蛋白之间的流量。 特定目的2：确定可溶性脂质转移扮演的角色 LPS外排和对获得LPS的细胞的反应中的蛋白质。 特定目的3：评估天然脂蛋白的相对重要性 从正常和急性期等离子体的类别作为细胞相关的受体 LPS。特定目的4：研究LPS外排对细胞反应的影响 LPS。