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 家族由抑制性受体和激活性受体组成；后者通过 DAP12 进行交互和发出信号。在审查期间，我们继续剖析与 DAP12 信号传导相关的近端事件。这项工作的结果包括定义 129/Sv 背景小鼠中 DAP12 信号传导的明显缺陷，该缺陷可以深刻影响基因靶向小鼠的分析，描绘 CD45 对 DAP12 信号传导的两个水平调节（DAP-12 本身的信号起始和去磷酸化），以及最近剖析非催化接头蛋白连接器的重叠使用，以激活 T 细胞 (LAT) 和 B 细胞激活连接子 (LAB)。 TREM-1 调节脓毒症，而 TREM-2 可以控制 DC、小胶质细胞和破骨细胞的发育。我们对 TREM 星团的研究已经发表了以下内容： 1) 鉴定 TREM 样转录物-1 (TLT-1)，一种不与 DAP-12 偶联但与 SHP-1 相互作用的蛋白质； 2) TLT-1作为隔离在α颗粒中的血小板特异性受体的表征； 3)血清中可溶性TLT-1的鉴定，以及胞外域晶体结构的解。我们还针对小鼠体内的 TLT-1，展示了其在体外血小板聚集中的作用，并定义了一些与其相互作用的蛋白质。尽管血小板和血栓形成可以调节炎症、癌症生长和转移以及适应性免疫，但我们选择不在我们的基础分配下提出进一步的 TLT-1 研究。然而，如果有足够的资源，我们将继续 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-/- 小鼠。