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).

该提案是为了回应通知号，而不是2009年《美国恢复和再投资法》的NOT-OD-09-088。我们要求对修订后的赠款申请的前两年1R01AI73718-01A2进行资金，并由NIAIDID批准的范围变化计划官。具体而言，我们建议通过DAP10/DAP12/FCR相关的激活受体（DAPAAR）阐明信号传导的分子机制，例如NK细胞中NKG2D和髓样细胞中整合素的NKG2D，以及为介导蛋白质的作用而建立介导蛋白质所必需的作用的作用。从DAP-ARARS发出的信号作为微生物发病机理中的敏感性基因座。在这种情况下，我们最近确定了VAV和DAP10/DAP12/FCR蛋白的关键新功能在从先天免疫受体中发出的转导信号中，包括NK细胞和髓样细胞中的激活受体。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（PI3K）进行了串扰，以扩大导致NK细胞毒性的信号。 VAV蛋白通过激活ITAM和非ITAM依赖性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中的一种新型范式。在这种情况下，包括我们的几个实验室的新发现揭示了一种先前意外的机制，其中整联蛋白和其他粘附受体利用DAP12和FCR来促进粘附和效应子响应。虽然增强中性粒细胞效应子反应，包括遵守整合素配体的细胞因子产生，脱粒和吞噬作用，这些新结果揭示了促炎刺激和粘附受体激活的共享信号传导模块。在这项修改后的提案中，我们旨在建立NKG2DDAP10-Proximal信号传导和VAV1-PI3K串扰的机制（AIM 1），并从DAP10/DAP12/FCR相关的激活受体（DAP-AARS）（DAP-AARS）（DAP-AARS）（DAP12/FCR）划定信号通路。几种编码蛋白质的基因的作用，对于介导从体内微生物发病机理中的DAP-AAS作为易感基因座发出的信号必不可少的作用（AIM 2）。