SCAVENGER RECEPTOR FUNCTION IN CHAPERONE-ELICITED ADAPTIVE IMMUNE RESPONSES

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 中心，但不一定是研究者所在的机构。 清道夫受体是结合和运输多种内源性和微生物配体的模式识别受体。我们目前研究的主要目的是确定清道夫受体调节白细胞免疫应答的机制，并可靶向调节白细胞免疫应答。具体来说，我们正在研究：1）清道夫受体A类（SR-A）如何将细菌和伴侣内化到抗原呈递细胞中，以及2）表达SR-A的白细胞如何促进卵巢癌。 我们的努力的很大一部分是针对目标1，这引起了我们的鉴定SR-A作为一种新的内吞受体的分子伴侣gp 96和CRT。随着SR-A-/-小鼠的使用，我们集中在阐明清道夫受体介导的伴侣蛋白的免疫学效应的机制。我们最近的数据表明，与gp 96和其他分子伴侣相反，CRT需要添加外源性佐剂来引发体内细胞毒性CD 8 + T细胞应答。这些数据发表在巴克等人（2008）中。我们的研究最近扩大到确定SR-A在细菌感染过程中的作用，使用来自SR-A-/-小鼠的树突状细胞（DC）。功能分析表明SR-A是革兰氏阴性菌E.大肠杆菌（Amiel等人，2007年）。目前的努力，现在针对阐明SR-A和另一个家庭的细胞受体的微生物产品，Toll样受体（TLR）之间的相互作用。本摘要中描述的研究以及其他初步数据是计划提交NIH资助的基础。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Scavenger receptors are pattern recognition receptors that bind and traffic a variety of endogenous and microbial ligands. The broad objective of our current studies is to define the mechanisms by which scavenger receptors modulate, and can be targeted to modulate, immune responses from leukocytes. Specifically, we are investigating: 1) how Scavenger Receptor Class-A (SR-A) functions to internalize bacteria and chaperones into antigen-presenting cells, and 2) how SR-A -expressing leukocytes contribute to ovarian cancer. A large part of our effort is directed towards Aim 1, which evokes from our identification of SR-A as a novel endocytic receptor for the molecular chaperones gp96 and CRT. With the use of SR-A-/- mice we have focused on elucidating the mechanisms by which scavenger receptors mediate the immunological effects of chaperones. Our recent data indicate that, in contrast to gp96 and other chaperones, CRT requires the addition of an exogenous adjuvant to elicit in vivo cytotoxic CD8+ T cell responses. These data were published in Bak et al. (2008). Our studies have recently expanded to identify the role of SR-A during bacterial infection with the use of dendritic cells (DCs) from SR-A-/- mice. Functional analyses demonstrated that SR-A is a critical phagocytic receptor for DC internalization of the gram-negative bacteria E. coli (Amiel et al., 2007). Current efforts are now directed at elucidating the interplay between SR-A and another family of cellular receptors for microbial products, the Toll-like receptors (TLRs). The studies described in this Abstract, together with other preliminary data, are the basis for a planned NIH grant submission.