Proximal signaling complexes in NK cell effector function and development

NK 细胞效应器功能和发育中的近端信号复合物

基本信息

批准号：
8085441
负责人：
Taku Kambayashi
金额：
$ 40万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-15 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8085441
关键词：
76-kDa SH2 domain-containing leukocyte protein Activated Natural Killer Cell Adaptor Signaling Protein Affect Attenuated Binding Biochemical Cell Maturation Cell membrane Cell physiology Cells Cellular biology Complex Data Defect Development Disease Environment Exhibits Failure Family member Goals Hematopoietic Immune Immune system In Vitro Jordan LCP2 gene Lead Leukocytes Light MHC Class I Genes Mediating Medical center Membrane Mitogen-Activated Protein Kinases Modeling Mus NK Cell Activation Natural Killer Cells Oranges Pathway interactions Pennsylvania Phenotype Phosphorylation Play Production Proteins Reagent Receptor Mediated Signal Transduction Receptor Signaling Recruitment Activity Regulation Research Role Self Tolerance Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Molecule T-Lymphocyte Testing Universities cell type cytokine cytotoxicity in vivo insight novel novel strategies pathogen receptor receptor binding research facility research study response tool tumor

项目摘要

DESCRIPTION (provided by applicant): This proposal describes a 5-year research plan focusing on the proximal signaling complexes that are formed downstream of natural killer (NK) cell activating receptors and how signaling pathways leading from these complexes affect NK cell effector function and development. NK cells are innate immune cells that defend the host from intracellular pathogens and tumors. Regulation of NK cell activation involves the expression of activating receptors that are finely counterbalanced by inhibitory MHC class I-binding receptors (e.g., Ly49 family members), which allow NK cells to achieve self tolerance. How the precise signaling pathways leading from NK cell activating receptors contribute to mature NK cell effector function and inhibitory receptor acquisition during development are not well understood. Signaling through activating immunoreceptors relies on the formation of a proximal multimolecular complex nucleated by the adaptor protein SH2 containing leukocyte protein of 76kD (SLP-76). Our preliminary data support an important role for SLP-76 in activating receptor-mediated NK cell effector signal transduction, which is critical for NK cell effector function and Ly49 receptor acquisition. In addition, our data suggest that NK cells also use an alternative mechanism that may be different from other hematopoietic cell types to localize SLP-76 to the plasma membrane and to initiate signal transduction. This alternative signal transduction pathway leading from SLP-76 may be important during NK cell development for the acquisition of Ly49 receptors. In this proposal, we hypothesize that SLP-76 mediates multiple signal transduction pathways downstream of NK cell activating receptors, which play differential roles in NK cell effector function and in the acquisition of Ly49 receptors. Our research plan starts with an examination of how proximal signaling complexes involving SLP-76 are formed in NK cells downstream of activating receptors. We will then examine how these signal transduction pathways contribute to the different NK cell effector functions and to NK cell acquisition of Ly49 receptors. The experiments described in this proposal will yield insight into the precise signal transduction pathways downstream of activating receptors in NK cells, which is essential for our understanding of how NK cells are activated in the periphery and achieve self tolerance through expression of Ly49 receptors. This information will allow us to devise novel strategies to modulate NK cell responses in multiple disease settings. Our expertise in signal transduction and NK cell biology together with our expert consultants (Drs. Jordan Orange, Tobias Baumgart, and Yoji Shimizu), and the quality of the research facilities at the University of Pennsylvania Medical Center comprise an ideal environment in which to conduct this proposed research plan. Thus, we believe that we are uniquely equipped with the tools/reagents and expertise to investigate this important aspect of NK cell biology. PUBLIC HEALTH RELEVANCE: Natural killer (NK) cells belong to the innate immune system and play a vital role in defending the host from intracellular pathogens and tumors. The goal of this proposal is to investigate how signal transduction pathways through activating receptors affect NK cell effector function and Ly49 receptor acquisition during development. Further understanding of how NK cells are activated in the periphery and achieve self tolerance through expression of Ly49 receptors will allow us to devise novel strategies to control NK cell responses in multiple disease settings.

描述（由申请人提供）：该提案描述了一项为期 5 年的研究计划，重点关注自然杀伤 (NK) 细胞激活受体下游形成的近端信号传导复合物，以及这些复合物导致的信号传导途径如何影响 NK 细胞效应器功能和发育。 NK 细胞是保护宿主免受细胞内病原体和肿瘤侵害的先天免疫细胞。 NK 细胞激活的调节涉及激活受体的表达，这些受体被抑制性 MHC I 类结合受体（例如 Ly49 家族成员）精细平衡，从而使 NK 细胞能够实现自我耐受。 NK 细胞激活受体引导的精确信号通路如何促进成熟 NK 细胞效应器功能和发育过程中抑制性受体的获得，目前尚不清楚。通过激活免疫受体的信号传导依赖于由含有 76kD 白细胞蛋白 (SLP-76) 的接头蛋白 SH2 成核的近端多分子复合物的形成。我们的初步数据支持 SLP-76 在激活受体介导的 NK 细胞效应信号转导中发挥重要作用，这对于 NK 细胞效应功能和 Ly49 受体获取至关重要。此外，我们的数据表明 NK 细胞还使用可能不同于其他造血细胞类型的替代机制将 SLP-76 定位到质膜并启动信号转导。这种源自 SLP-76 的替代信号转导途径可能在 NK 细胞发育过程中对于获得 Ly49 受体非常重要。在本提案中，我们假设 SLP-76 介导 NK 细胞激活受体下游的多个信号转导途径，这些途径在 NK 细胞效应功能和 Ly49 受体的获得中发挥不同的作用。我们的研究计划首先检查涉及 SLP-76 的近端信号复合物是如何在激活受体下游的 NK 细胞中形成的。然后我们将研究这些信号转导途径如何促进不同的 NK 细胞效应功能以及 NK 细胞获取 Ly49 受体。该提案中描述的实验将深入了解 NK 细胞激活受体下游的精确信号转导途径，这对于我们了解 NK 细胞如何在外周激活并通过 Ly49 受体的表达实现自我耐受至关重要。这些信息将使我们能够设计出新的策略来调节多种疾病环境下的 NK 细胞反应。我们在信号转导和 NK 细胞生物学方面的专业知识以及我们的专家顾问（Jordan Orange 博士、Tobias Baumgart 和 Yoji Shimizu）以及宾夕法尼亚大学医学中心的研究设施质量构成了进行研究的理想环境。本提议的研究计划。因此，我们相信我们拥有独特的工具/试剂和专业知识来研究 NK 细胞生物学的这一重要方面。公共健康相关性：自然杀伤 (NK) 细胞属于先天免疫系统，在保护宿主免受细胞内病原体和肿瘤侵害方面发挥着至关重要的作用。该提案的目标是研究通过激活受体的信号转导途径如何影响 NK 细胞效应器功能和发育过程中 Ly49 受体的获得。进一步了解 NK 细胞如何在外周被激活并通过 Ly49 受体的表达实现自我耐受，将使我们能够设计出新的策略来控制多种疾病环境中 NK 细胞的反应。