Identification of BATF function and targets during NK cell activation

NK 细胞激活过程中 BATF 功能和靶标的鉴定

• 批准号: 10494220
• 负责人: BARBARA L. KEE
• 金额: $ 24.6万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10494220
• 关键词: Activated Natural Killer Cell; Address; Bacteria; Binding; Binding Sites; CD8-Positive T-Lymphocytes; Cell physiology; Cell surface; Cells; Chromatin; Chronic; Computer Analysis; Coronavirus; Cytokine Receptors; Cytokine Signaling; Data; Disease; Environment; Exploratory/Developmental Grant; Family; Foundations; Future; Gene Expression; Genes; Genetic Transcription; Germ Lines; Goals; Grant; Herpesviridae; Histocompatibility; IRF4 gene; Immune response; Infection; Inflammatory; Interferon Type II; Interleukin-12; Interleukin-18; Knowledge; Lead; Ligands; Malignant - descriptor; Metastatic Melanoma; Metastatic to; Methods; Modeling; Murid herpesvirus 1; Mus; NK Cell Activation; Natural Killer Cells; Neoplasm Metastasis; Pathogenicity; Pathway interactions; Phase; Play; Production; Receptor Signaling; Role; Series; Signal Pathway; Signal Transduction; Signaling Protein; Site; Solid Neoplasm; Stress; Testing; Therapeutic; Time; Transcription Factor AP-1; Transcriptional Activation; Viral Cancer; Virus; Virus Diseases; XCL1 gene; anti-cancer; cell motility; chemokine; cytokine; cytotoxicity; immune checkpoint blockade; insight; melanoma; member; migration; novel; pathogen; programs; receptor; response; transcription factor; transcription regulatory network; transcriptome sequencing; tumor; tumor microenvironment

Project Summary Natural killer (NK) cells play essential roles in the immune response to intracellular pathogens, including viruses and bacteria, and form an important defense against malignant transformation and metastasis. NK cells are activated when they detect an imbalance in the signals from receptors on their cell surface, either a loss of inhibitory signals or activation through activating receptors including cytokine receptors. Alterations in these signaling pathways impact the transcriptional regulatory networks that contribute to NK cell activation and effector function. At the present time there is a gap in our knowledge of the major transcription factors that are impacted by these signaling pathways and how they modulate NK cell function. In this R21 application, we present data to support the hypothesis that Batf, the founding member of the AP-1 family of transcription factors, is induced by proinflammatory cytokine signaling in NK cells and impacts multiple aspects of the NK cell response. In aim 1, we will test the hypothesis that Batf regulates key genes involved in NK cell expansion, survival, and effector function by identifying direct Batf targets during the response to mouse cytomegalovirus. In aim 2, we will test the hypothesis that Batf plays unique roles in different NK cell activating contexts by testing the requirement for Batf in the NK cell response to metastatic melanoma and in a solid tumor model that relies on NK cell migration and chemokine production. Taken together, these studies will provide a broad view of the requirements for Batf in distinct NK cell activation contexts and lead to the identification of Batf targets that underlie its essential functions.

项目概要 自然杀伤 (NK) 细胞在针对细胞内病原体的免疫反应中发挥重要作用， 包括病毒和细菌，形成防止恶性转化的重要防御 和转移。当 NK 细胞检测到信号不平衡时，它们就会被激活 细胞表面的受体，要么失去抑制信号，要么通过激活而激活 受体包括细胞因子受体。这些信号通路的改变会影响 有助于 NK 细胞激活和效应功能的转录调控网络。在 目前我们对主要转录因子的了解存在差距 受这些信号通路及其调节 NK 细胞功能的影响。在这个R21 应用程序中，我们提供数据来支持这样的假设：Batf，该组织的创始成员 AP-1 转录因子家族，由 NK 细胞中的促炎细胞因子信号传导诱导 并影响 NK 细胞反应的多个方面。在目标 1 中，我们将检验以下假设： Batf 通过以下方式调节参与 NK 细胞扩增、存活和效应功能的关键基因 识别小鼠巨细胞病毒反应过程中的直接 Batf 靶点。在目标 2 中，我们将 通过测试验证 Batf 在不同 NK 细胞激活环境中发挥独特作用的假设 NK 细胞对转移性黑色素瘤和实体瘤的反应需要 Batf 依赖 NK 细胞迁移和趋化因子产生的模型。综合起来，这些研究 将提供 Batf 在不同 NK 细胞激活环境中的需求的广泛视图，以及 导致识别其基本功能基础的 Batf 目标。