SCAVENGER RECEPTOR FUNCTION IN CHAPERONE-ELICITED ADAPTIVE IMMUNE RESPONSES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 清道夫受体是一种模式识别受体，可以结合和运输各种内源性和微生物配体。我们目前研究的主要目标是确定清道夫受体调节和靶向调节白细胞免疫反应的机制。具体地说，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为抗原提呈细胞，以及2)表达SR-A的白细胞如何在卵巢癌中发挥作用。 我们的很大一部分努力是针对目标1，这引起了我们对SR-A作为分子伴侣gp96和CRT的新的内吞受体的鉴定。利用SR-A-/-小鼠，我们致力于阐明清道夫受体介导伴侣蛋白免疫效应的机制。我们最近的数据表明，与gp96和其他伴侣不同，CRT需要添加外源性佐剂来在体内诱导细胞毒性CD8+T细胞反应。这些数据发表在Bak等人的杂志上。(2008年)。我们的研究最近扩展到使用来自SR-A-/-小鼠的树突状细胞(DC)来确定SR-A在细菌感染中的作用。功能分析表明，SR-A是革兰氏阴性杆菌DC内化的关键吞噬受体(Amiel等人，2007年)。目前的研究方向是阐明SR-A与微生物产物的另一类细胞受体--Toll样受体(TLRs)之间的相互作用。本摘要中描述的研究与其他初步数据一起，是计划中的NIH拨款提交的基础。

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.