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。关于该项目的最新数据发表在Bak等人的杂志上。(2008)和Tewalt等人。(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。功能分析阐明了SR-A和Toll样受体(TLR)之间对革兰氏阴性杆菌DC内化的一种新的相互作用(Amiel等人，2009年)。目前的努力是将这些研究扩展到铜绿假单胞菌，这是一种对囊性纤维化(CF)患者的发病有重要贡献的细菌病原体。本摘要中描述的科布雷资助的研究构成了我们随后资助的NIH RO1拨款的基础。

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. Recent data on this project were published in Bak et al. (2008) and Tewalt 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 elucidated a novel interplay between SR-A and the Toll-like receptors (TLR) for DC internalization of the gram-negative bacteria E. coli (Amiel et al., 2009). Current efforts are now directed at extending these investigations to the bacteria Pseudomonas aeruginosa, which is a bacterial pathogen that substantially contributes to the pathogenesis of cystic fibrosis (CF) patients. The COBRE-funded studies described in this Abstract formed the basis for our subsequently-funded NIH RO1 grant.