Determining the Molecular Mechanism of Covalently Linked TLR Agonists

确定共价连接的 TLR 激动剂的分子机制

• 批准号: 9240573
• 负责人: Aaron P Esser-Kahn
• 金额: $ 40.33万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-08 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9240573
• 关键词: Adjuvant; Affinity; Agonist; Alpha Cell; Antibodies; Antibody Affinity; Antibody Diversity; Antibody Response; Antibody titer measurement; Antigen Presentation; Antigen-Presenting Cells; Avidity; Binding; Biological; Cells; Critical Pathways; Data; Diffusion; Elements; Ensure; Epitopes; Exclusion; Goals; Immune; Immune response; Immune system; Indoles; Inflammation; Inflammatory Response; Innate Immune System; Kinetics; Knock-out; Knowledge; Lead; Learning; Length; Link; Location; Mediating; Mediation; Membrane; Modeling; Molecular; Molecular Biology; Music; Nature; Pathway interactions; Pattern recognition receptor; Play; Proteins; Publishing; Receptor Activation; Receptor Signaling; Reporter; Research; Research Personnel; Role; Safety; Signal Transduction; Specificity; Subunit Vaccines; Surface; Synthesis Chemistry; System; T cell response; TLR2 gene; TLR4 gene; TLR7 gene; Testing; Time; Toll-like receptors; Translating; Vaccine Adjuvant; Vaccine Design; Vaccines; Vaccinia; Viral Vaccines; Work; base; cell type; chemical synthesis; crosslink; cytokine; design; immune activation; improved; innovation; novel; novel vaccines; public health relevance; receptor; response; safety testing; spatiotemporal; success; synergism; tool

 DESCRIPTION (provided by applicant): Many viral vaccines stimulate the immune system through a synergistic combination of pattern recognition receptors. These combinations of agonists are critical for long-lived antibody and T- cell responses. These multi-agonist responses could be applied as new adjuvants, but the pathways and mechanisms through which they operate remain unclear. Our goal is to elucidate a mechanistic pathway for adjuvant synergies resulting from the molecular activation of two receptors by two covalently linked Toll-like Receptor (TLR) agonists (Dual_TLRs) on antigen presenting cells. We will determine the location of a set of synergies and the mechanism by which they occur. We will test the safety and efficacy of our synergistic adjuvants using model vaccines. We will use a combination of synthetic chemistry and molecular biology tools to probe physical and biological mechanisms for the synergistic activation of two TLRs. In this application, we study the enhanced activity and antibody response of two TLR agonists that are linked together. Previously, we showed that linking agonists of distinct TLRs (e.g. TLR2_TLR9) leads to increased activation. Vaccines adjuvanted with Dual_TLR agonists improve the breadth and intensity of antibody response. Moreover, these synergies are controlled by the linker-length and receptor identity implying control at the molecular level by physical phenomenon. Studying the mechanism of Dual_TLR agonists will result in fundamental understanding of signaling synergies within cells as well as an understanding of the mechanism that links cellular responses to antibody diversity mediated by TLR signaling. With this fundamental knowledge, it will be easier to apply the knowledge gained from viral vaccines to the designing new adjuvants.

 描述(申请人提供)：许多病毒疫苗通过模式识别受体的协同组合刺激免疫系统。这些激动剂的组合对长寿抗体和T细胞反应至关重要。这些多激动剂反应可以作为新的佐剂应用，但它们的作用途径和机制尚不清楚。我们的目标是阐明由抗原提呈细胞上的两个共价连接的Toll样受体激动剂(Dual_TLRs)分子激活两个受体而产生的佐剂协同效应的机制。我们将确定一套协同效应的地点和产生机制。我们将使用模型疫苗测试我们的协同佐剂的安全性和有效性。我们将使用合成化学和分子生物学工具的组合来探索两个TLR协同激活的物理和生物学机制。在这个应用中，我们研究了两个连接在一起的TLR激动剂的增强活性和抗体反应。以前，我们已经证明不同TLRs的连接激动剂(例如TLR2_TLR9)会导致激活增加。用双TLR激动剂佐剂的疫苗可提高抗体应答的广度和强度。此外，这些协同作用受连接子长度和受体同一性的控制，这意味着在分子水平上受物理现象的控制。研究Dual_TLR激动剂的作用机制将有助于从根本上理解细胞内的信号协同作用以及TLR信号介导的抗体多样性与细胞反应之间的联系机制。有了这些基础知识，就更容易将从病毒疫苗中获得的知识应用于设计新的佐剂。