LPS EFFLUX HOST CELLS TO PLASMA LIPOPROTEINS

描述（改编自申请人摘要）：细菌脂多糖 (LPS)是有效的免疫调节化合物，在革兰氏阴性菌感染过程中， 阴性感染，可能在诱导脓毒症中起主要作用。 冲击.因此，全面了解宿主机制涉及的 运输、解毒和减弱免疫调节的这些强大的 细菌膜成分将是配制有效的 感染性休克的干预策略。以前的工作从几个 实验室已经表明，从革兰氏阴性菌表面释放的LPS 细菌似乎有两种命运：LPS可能与白细胞结合， 炎症反应，或者它们与血浆脂蛋白结合， 减弱LPS生物活性并促进清除。最近的工作在博士。 基特的实验室表明，在宿主体内还有一种成分， 对LPS的反应LPS可以从白细胞表面除去， 与血浆脂蛋白复合或与纯化的高密度脂蛋白 脂蛋白（HDL）。这种现象被称为LPS流出。感应 急性期反应物的释放可能会增强LPS的流出。最后， LPS外排可能是下调宿主炎症反应的原因。 对LPS的反应提出了四个具体目标来解决这一假设， LPS流出减少细胞对LPS的反应。 具体目标1：确定细胞表面蛋白在LPS中所起的作用 细胞和脂蛋白之间的交通。 具体目标2：确定可溶性脂质转移所起的作用 LPS流出和对获得LPS的细胞的反应中的蛋白质。 具体目标3：评估天然脂蛋白的相对重要性 作为细胞相关受体的正常和急性期血浆的类别 LPS。具体目标4：研究LPS流出对细胞应答的影响， LPS。

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.