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: 7876860
• 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/7876860
• 关键词: Adaptor Signaling Protein; Adherence; Adhesions; American; Antigen Presentation; Applications Grants; Cells; Complex; Coupled; Cross Presentation; Cytolysis; Data; Dendritic Cells; Employee Strikes; Feedback; Funding; Genes; ITAM; Immune response; Immune system; 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; Pathway interactions; 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; adaptive immunity; 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《美国复苏和再投资法案》NOT-OD-09-088号通知的回应。我们要求资助修订后的赠款申请1 R 01 AI 73718 - 01 A2的前两年，并由NIAID计划官员批准范围的变化。具体而言，我们建议阐明DAP 10/DAP 12/FcR相关激活受体（DAPAAR），如NK细胞中的NKG 2D和髓系细胞中的整合素的信号传导的分子机制，并建立几个基因编码的蛋白质的作用，这些蛋白质是介导DAP-AAR作为微生物发病机制中的易感基因座发出的信号所必需的。在这种情况下，我们最近已经确定了Vav和DAP 10/DAP 12/FcR蛋白在转导源自先天免疫受体的信号中的关键新功能，包括NK细胞和骨髓细胞中的活化受体。基于这些初步数据，我们提出了一个模型，其中Vav和磷酸肌醇3-激酶（PI 3 K）参与串扰放大信号，导致NK细胞毒性。Vav蛋白通过激活ITAM依赖性和非ITAM依赖性信号传导来控制先天性免疫应答的概念代表了信号转导和细胞激活的新范例。在这种情况下，包括我们在内的几个实验室的惊人新发现揭示了一种以前未预料到的机制，其中整合素和其他粘附受体利用DAP 12和FcR促进粘附和效应器反应。虽然增强中性粒细胞效应器的反应，包括细胞因子的产生，脱粒，并通过粘附整合素配体的吞噬作用已被赞赏超过30年，这些新的结果揭示了共同的信号传导模块激活的促炎刺激和粘附受体。在这个修改后的提案中，我们的目标是建立NKG 2DDAP 10近端信号传导和Vav 1-PI 3 K串扰的机制（目标1），并描绘来自DAP 10/DAP 12/FcR相关激活受体（DAP-AAR）的信号传导途径，并建立几个编码蛋白质的基因的作用，这些蛋白质是介导DAP-AAR作为体内微生物发病机制中的易感基因座发出的信号所必需的（目标2）。