Defining the pathways activated by Toll-like Receptors to stimulate immunity

定义 Toll 样受体激活的途径以刺激免疫力

• 批准号: 10553667
• 负责人: JONATHAN C KAGAN
• 金额: $ 53.1万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-13 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10553667
• 关键词: Antitumor Response; Biology; CD14 Antigen; CD8-Positive T-Lymphocytes; Cells; Complex; Curiosities; Dangerousness; Data; Dedications; Dendritic Cells; Detection; Enzymes; Event; Family; Funding; Gene Expression; Genetic Transcription; Glycolysis; Glycolysis Induction; Glycolysis Pathway; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Immune response; Immunity; In Vitro; Infection; Inflammatory; Interferons; Investigation; Knowledge; Life; MAP Kinase Gene; Macrophage; Malignant Neoplasms; Medial; Mediating; Metabolic; Microbe; Motion; Mus; NF-kappa B; Pathway interactions; Phosphotransferases; Proteins; Receptor Signaling; Regulation; Research Proposals; Role; Signal Pathway; Signal Transduction; Site; Structure; System; T-Lymphocyte; TBK1 gene; TLR3 gene; TLR4 gene; TRAF6 gene; Tissues; Toll-Like Receptor Pathway; Toll-like receptors; Tumor Antigens; Tumor Immunity; Work; adaptive immunity; aerobic glycolysis; cancer immunotherapy; immune activation; in vitro activity; innate immune pathways; innovation; novel; receptor; recruit; response; scaffold; synthetic biology; transcription factor

Project Summary The goal of this proposal is to identify how Toll-like Receptors (TLRs) stimulate diverse cellular responses in macrophages and dendritic cells (DCs), and to understand how these responses influence DC-based cancer immunotherapies. The ability of TLRs to induce inflammatory gene expression has been under investigation for twenty years, with distinct signaling pathways mediated by the MyD88 and TRIF adaptors explaining all transcriptional responses. It has only recently become appreciated that TLRs also drive metabolic changes in responding cells, such as the rapid induction of aerobic glycolysis. During the previous funding period, we discovered that the TLR-induced myddosome complex contains two classes of proteins. One class is necessary for myddosome assembly (e.g. MyD88) and represents the core of this signaling structure. The second class is not necessary for myddosome assembly (e.g. TRAF6), but rather operates to recruit enzymes that diversify the effector functions of the myddosome. Specifically, we identified the kinase TBK1 as a myddosome component that is recruited by TRAF6 and is dedicated specifically to induce glycolysis. The myddosome therefore serves as a subcellular site of signals that activate diverse cellular responses. Our understanding of how these activities are regulated in vitro and their impact on T cell mediated protective immunity remains limited. In addition to the myddosome, select TLRs (e.g. TLR4 and TLR3) engage the triffosome. The central triffosome regulator is TRIF, which stimulates interferon (IFN) responses, NF-kB and MAPK activation, necroptosis and glycolysis. While the importance of TRIF in immunity has long-been recognized, the means by which it activates these diverse responses is unclear. This gap in knowledge is not merely an academic curiosity, as TRIF is essential for the ability of the LPS receptor TLR4 to stimulate adaptive immunity. Understanding regulatory events that stimulate myddosome- and TRIF-dependent responses will enable discussions of how TLRs drive protective immunity against infection and cancer. In this application, we propose to explore myddosome activities in vitro and in the context of cancer immunotherapies (Aim 1). In Aim 2, we offer an innovative synthetic biology-based approach to define the mechanisms of TRIF signaling and how these mechanisms relate to those induced by complementary innate immune pathways. Our focus on the two major signaling pathways activated by TLRs should provide an operational view of this important family of receptors.

项目摘要 该提案的目的是确定Toll样受体（TLR）如何刺激各种细胞反应 巨噬细胞和树突状细胞（DC），并了解这些反应如何影响基于DC的癌症 免疫疗法。 TLR诱导炎症基因表达的能力正在研究中 二十年，由MyD88和Trif适配器介导的独特信号通路解释了所有 转录响应。直到最近，TLR也推动了代谢变化，直到最近才得知 反应细胞，例如有氧糖酵解的快速诱导。在上一个资金期间，我们 发现TLR诱导的myddosome络合物包含两类蛋白质。一个课是必要的 对于myddosome组装（例如MyD88），代表该信号结构的核心。第二堂课是 Myddosome组装（例如TRAF6）不是必需的，而是为了招募多样化的酶 myddosome的效应器功能。具体而言，我们将激酶TBK1识别为myddosome组件 这是由TRAF6招募的，专门用于诱导糖酵解。因此，myddosome可以使用 作为激活各种细胞反应的信号的亚细胞位点。我们对这些活动的理解 在体外调节，它们对T细胞介导的保护性免疫的影响仍然有限。 除MyDdosome外，还选择TLR（例如TLR4和TLR3）参与Triffosome。中央triffosom 调节剂是TRIF，它刺激干扰素（IFN）反应，NF-KB和MAPK激活，坏死性和 糖酵解。虽然TRIF在免疫力中的重要性已长期认可，但它激活的手段 这些多样化的反应尚不清楚。知识的差距不仅是学术的好奇心，因为Trif是 LPS受体TLR4刺激适应性免疫的能力至关重要。了解监管 刺激myddosome-和Trif依赖性响应的事件将使TLRS驱动器如何讨论 防止感染和癌症的保护性免疫。在此应用程序中，我们建议探索myddosome 体外和癌症免疫疗法的活动（AIM 1）。在AIM 2中，我们提供创新的合成 基于生物学的方法来定义TRIF信号的机制以及这些机制与这些机制的关系 由互补的先天免疫途径诱导。我们专注于激活的两个主要信号通路 TLR应提供这一重要受体家族的操作视图。