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: 10209029
• 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/10209029
• 关键词: Antitumor Response; Biology; CD14 Antigen; CD8-Positive T-Lymphocytes; Cells; Complex; Curiosities; Dangerousness; Data; Dendritic Cells; Detection; Enzymes; Event; Family; Funding; Gene Expression; Genetic Transcription; Glycolysis; Glycolysis Pathway; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Immune response; Immunity; In Vitro; Infection; Inflammatory; Interferons; Investigation; Knowledge; Life; MAP Kinase Gene; Malignant Neoplasms; 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; base; cancer immunotherapy; immune activation; in vitro activity; innate immune pathways; innovation; macrophage; 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.

项目总结