Signal Transduction of Paired Inhibitory Receptors of NK

NK 成对抑制性受体的信号转导

• 批准号: 7338380
• 负责人: Daniel W. McVicar
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7338380
• 关键词: Signal; Transduction; Paired; Inhibitory; Receptors

The Ly49 and KIR families are comprised of both inhibitory and activating receptors; the latter interacting and signaling through DAP12. We have continued our dissection of the proximal events associated with DAP12 signaling over the review period. The result of this work includes the definition of an apparent defect in DAP12 signaling in mice of the 129/Sv background that can profoundly effect the analysis of gene targeted mice, delineation of two levels of regulation of DAP12 signaling by CD45 (signal initiation and dephosphorylation of DAP-12 itself), and most recently, dissection of the overlapping use of the non-catalytic adaptor proteins Linker for Activation of T cells (LAT) and the Linker for Activation of B cells (LAB). TREM-1 regulates sepsis whereas TREM-2 can control the development of DC, microglia and osteoclasts. Our studies of the TREM cluster have led to publications regarding; 1) the identification of TREM-like transcript-1 (TLT-1), a protein that does not couple to DAP-12 but instead interacts with SHP-1; 2) characterization of TLT-1 as a platelet specific receptor sequestered in alpha granules; and 3) identification of soluble TLT-1 in serum, and solution of the crystal structure of the extracellular domain. We have also targeted TLT-1 in mice, shown its role in platelet aggregation in vitro, and defined some proteins that interact with it. Although platelets and thrombosis can regulate inflammation, cancer growth and metastasis, and adaptive immunity, we have chosen not to propose further TLT-1 studies under our base allocation here. If however, sufficient resources were available, we would continue biochemical study of TLT-1. We are currently, evaluating our TLT-1-/- mice in collaboration with a former fellow from our lab.

LY49和KIR家族由抑制性和激活受体组成。后者通过DAP12进行交互和信号传导。我们继续对审查期间与DAP12信令相关的近端事件进行解剖。这项工作的结果包括在129/SV背景中DAP12信号传导中明显缺陷的定义，可以深刻影响对基因靶向小鼠的分析，CD45对DAP12信号的两个级别的划定（信号启动和信号启动和dephossection for dap-12本身的dephoration for Dephoration for dip-dap-12 insection），以及最近期的distration distration for of depativation for dip-12 T细胞（LAT）和B细胞激活的接头（实验室）。 TREM-1调节败血症，而TREM-2可以控制直流，小胶质细胞和破骨细胞的发展。我们对TREM群集的研究导致了有关的出版物； 1）鉴定TREM样转录1（TLT-1），这种蛋白质不会偶联到DAP-12，而是与SHP-1相互作用； 2）将TLT-1表征为在α颗粒中隔离的血小板特异性受体； 3）在血清中鉴定可溶性TLT-1，以及细胞外域的晶体结构的溶液。我们还针对小鼠中的TLT-1，显示了其在体外血小板聚集中的作用，并定义了一些与之相互作用的蛋白质。尽管血小板和血栓形成可以调节炎症，癌症的生长和转移以及适应性免疫，但我们选择不在此基础分配下提出进一步的TLT-1研究。但是，如果有足够的资源可用，我们将继续对TLT-1的生化研究。目前，我们正在与我们实验室的一位前研究员合作评估我们的TLT-1 - / - 鼠标。