MECHANISMS OF SIGNALING BY ACTIVATING RECEPTORS IN INNATE IMMUNE SYSTEMS CELLS

通过激活先天免疫系统细胞中的受体来发出信号的机制

• 批准号: 7741304
• 负责人: WOJCIECH A SWAT
• 金额: $ 38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-19 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7741304
• 关键词: Adaptor Signaling Protein; Address; Adherence; Adhesions; American; Antigen Presentation; Applications Grants; Cells; Complex; Coupled; Cytolysis; Data; Dendritic Cells; Employee Strikes; Feedback; Funding; Genes; ITAM; Immune response; Immune system; Immunity; Immunologic Receptors; In Vitro; Inflammatory; Inflammatory Response; Integrins; Ligands; Mediating; Modality; Modeling; Molecular; Myeloid Cell Activation; Myeloid Cells; National Institute of Allergy and Infectious Disease; Natural Killer Cells; Pathogenesis; Pattern recognition receptor; Phagocytosis; Phosphatidylinositols; Phosphotransferases; Predisposition; Production; Proteins; Receptor Cell; Receptor Signaling; Recovery; Recruitment Activity; Regulation; Respiratory Burst; Role; Signal Pathway; Signal Transduction; Stimulus; Stress; TYROBP gene; Virus; Work; adhesion receptor; base; cytokine; cytotoxic; cytotoxicity; in vivo; macrophage; microbial; neoplastic cell; neutrophil; novel; pathogen; programs; receptor; response; tumor

This proposal is in response to Notice Number NOT-OD-09-088 of the American Recovery and Reinvestment Act of 2009. We request funding for the first two years of the revised grant application 1R01AI73718-01A2, with changes in scope approved by the NIAID Program Officer. Specifically, we propose to elucidate the molecular mechanism of signaling by DAP10/DAP12/FcR-associated activating receptors (DAPAARs), such as NKG2D in NK cells and integrins in myeloid cells, and to establish the role for several genes encoding proteins essential for mediating signals emanating from DAP-AARs as susceptibility loci in microbial pathogenesis. In this context, we have recently identified critical new functions of Vav and DAP10/DAP12/FcR proteins in transducing signals emanating from innate immune receptors including activating receptors in NK cells and myeloid cells. Based on these preliminary data, we propose a model in which Vav and Phosphoinositide 3-kinase (PI3K) engage in crosstalk to amplify signals leading to NK cytotoxicity. The concept that Vav proteins control innate immune responses by activating both ITAM- and non-ITAM-dependent signaling represents a novel paradigm in signal transduction and cellular activation. In this context, striking new findings from several labs including ours reveal a previously unanticipated mechanism in which integrins and other adhesion receptors utilize DAP12 and FcR to promote both adhesion and effector responses. While the augmentation of neutrophil effector responses including cytokine production, degranulation, and phagocytosis by adherence to integrin ligands has been appreciated for over 30 years, these new results reveal shared signaling modules activated by both proinflammatory stimuli and adhesion receptors. In this modified proposal, we aim to establish the mechanism of NKG2DDAP10-proximal signaling and Vav1-PI3K crosstalk (Aim 1), and to delineate signaling pathways emanating from the DAP10/DAP12/FcR-associated activating receptors (DAP-AARs) and establish the role for several genes encoding proteins essential for mediating signals emanating from DAP-AARs as susceptibility loci in microbial pathogenesis in vivo (Aim 2).

该提案是对2009年《美国复苏与再投资法案》NOT-OD-09-088号公告的回应。我们请求为修订后的拨款申请1R01AI73718-01A2的头两年提供资金，并经NIAID项目官员批准更改范围。具体地说，我们建议阐明DAP10/DAP12/FCR相关激活受体(DAPAARs)信号的分子机制，如NK细胞中的NKG2D和髓系细胞中的整合素，并确定几个编码DAP-AARs发出的信号所必需的蛋白质的基因在微生物发病中的易感基因的作用。在此背景下，我们最近发现了Vav和DAP10/DAP12/FCR蛋白在先天免疫受体信号传导中的关键新功能，包括激活NK细胞和髓系细胞中的受体。基于这些初步数据，我们提出了一个模型，在该模型中，Vav和磷脂酰肌醇3-激酶(PI3K)进行串扰，以放大导致NK细胞毒的信号。Vav蛋白通过激活ITAM依赖和非ITAM依赖的信号来控制先天免疫反应的概念代表了信号转导和细胞激活的新范式。在这种背景下，包括我们在内的几个实验室的惊人新发现揭示了一个以前没有预料到的机制，即整合素和其他黏附受体利用DAP12和FCR来促进黏附和效应器反应。虽然通过与整合素配体的黏附来增强中性粒细胞效应反应，包括细胞因子的产生、脱颗粒和吞噬作用，已经被认识到超过30年，但这些新的结果揭示了由促炎刺激和黏附受体激活的共同的信号模块。在这个修改的方案中，我们的目标是建立NKG2DDAP10-近端信号和Vav1-PI3K串扰的机制(Aim 1)，并描述DAP10/DAP12/FCR相关激活受体(DAP-AARs)发出的信号通路，并建立几个编码DAP-AARs发出的信号所必需的蛋白质的基因作为体内微生物发病的易感基因(Aim 2)。