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：
8277906
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/8277906
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.

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，该计划重点是近端信号传导复合物，这些信号传导复合物是自然杀伤（NK）细胞激活受体的下游形成的，以及从这些复合物引导的信号通路如何影响NK细胞效应器功能和开发。 NK细胞是固有的免疫细胞，捍卫宿主免受细胞内病原体和肿瘤的影响。 NK细胞激活的调节涉及激活受体的表达，这些受体通过抑制性MHC I类结合受体（例如LY49家族成员）在抑制性MHC中平衡，这使NK细胞得以实现自耐力。在发育过程中，从NK细胞激活受体导致的精确信号通路如何促进成熟的NK细胞效应子功能和抑制受体的获取。通过激活免疫感受器的信号传导取决于由含有76KD（SLP-76）的白细胞蛋白的衔接蛋白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激活受体介导的NK细胞效应器信号转导的重要作用，这对于NK细胞效应器功能和LY49受体获取至关重要。此外，我们的数据表明，NK细胞还使用一种替代机制，该机制可能与其他造血细胞类型不同，以将SLP-76定位于质膜并启动信号转导。从SLP-76导致的这种替代信号转导途径在获得LY49受体的NK细胞发育过程中可能很重要。在此提案中，我们假设SLP-76介导了NK细胞激活受体下游的多个信号转导途径，这些途径在NK细胞效应函数和获取LY49受体中起差异作用。我们的研究计划首先研究如何在激活受体下游的NK细胞中形成涉及SLP-76的近端信号传导复合物。然后，我们将研究这些信号转导途径如何有助于不同的NK细胞效应子函数和NK细胞的采集Ly49受体。本提案中描述的实验将深入了解NK细胞中激活受体下游的精确信号转导途径，这对于我们了解如何在周围激活NK细胞并通过LY49受体的表达实现自耐力至关重要。这些信息将使我们能够制定新的策略来调节多种疾病环境中的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博士和Yoji Shimizu），以及宾夕法尼亚大学医学中心的研究设施质量，包括一个理想的环境，在其中制定了这一建议的研究计划。因此，我们认为我们拥有独特的配备工具/试剂和专业知识，以研究NK细胞生物学的这一重要方面。