Mechanisms of Nanomaterials-based Combination Adjuvants

纳米材料复合佐剂的作用机制

基本信息

批准号：
10586948
负责人：
Jai Rudra
金额：
$ 51.16万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-05 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586948
关键词：
Acetylmuramyl-Alanyl-Isoglutamine Adjuvant Agonist Antigen Presentation Antigens Autophagocytosis CD8-Positive T-Lymphocytes Cell Maturation Cell physiology Cells Cellular Immunity Charge Chemicals Chemistry Dendritic Cells Dendritic cell activation Development Disease Dissection Emulsions Ensure Experimental Designs Flow Cytometry Formulation Goals Human Hydrophobicity Immune Immune response Immune signaling Immunity Immunize Immunologic Adjuvants Immunology procedure Individual Infection Inflammation Innate Immune Response Investigation Knockout Mice Licensing Lung MHC Class I Genes Mediating Metabolism Molecular Morphology Mus Natural Immunity Osmosis Outcome Oxidative Stress Pathway interactions Pattern Pattern recognition receptor Peptides Phenotype Production Property Safety Signal Pathway Signal Transduction Small Interfering RNA Subunit Vaccines T cell response T-Lymphocyte TLR2 gene Testing Tissues Toll-like receptors Transgenic Organisms Tuberculosis Vaccination Vaccine Adjuvant Vaccines adaptive immune response adaptive immunity aluminum sulfate cell injury combinatorial cytokine design dosage efficacy validation immunogenicity improved in vivo insight microbial mouse model nanofiber nanomaterials pathogen receptor response self assembly stoichiometry synergism tissue resident memory T cell transcriptome sequencing translational potential vaccine response

Acetylmuramyl-Alanyl-Isoglutamine Adjuvant Agonist Antigen Presentation Antigens Autophagocytosis CD8-Positive T-Lymphocytes Cell Maturation Cell physiology Cells Cellular Immunity Charge Chemicals Chemistry Dendritic Cells Dendritic cell activation Development Disease Dissection Emulsions Ensure Experimental Designs Flow Cytometry Formulation Goals Human Hydrophobicity Immune Immune response Immune signaling Immunity Immunize Immunologic Adjuvants Immunology procedure Individual Infection Inflammation Innate Immune Response Investigation Knockout Mice Licensing Lung MHC Class I Genes Mediating Metabolism Molecular Morphology Mus Natural Immunity Osmosis Outcome Oxidative Stress Pathway interactions Pattern Pattern recognition receptor Peptides Phenotype Production Property Safety Signal Pathway Signal Transduction Small Interfering RNA Subunit Vaccines T cell response T-Lymphocyte TLR2 gene Testing Tissues Toll-like receptors Transgenic Organisms Tuberculosis Vaccination Vaccine Adjuvant Vaccines adaptive immune response adaptive immunity aluminum sulfate cell injury combinatorial cytokine design dosage efficacy validation immunogenicity improved in vivo insight microbial mouse model nanofiber nanomaterials pathogen receptor response self assembly stoichiometry synergism tissue resident memory T cell transcriptome sequencing translational potential vaccine response

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项目摘要

PROJECT SUMMARY The discovery of pattern recognition receptors (PRRs), including toll-like receptors (TLRs) and NOD-like receptors (NLRs) has led to the investigation of molecular agonists of innate immunity in adjuvant formulations. An emerging paradigm is that careful selection of adjuvant combinations can result in complementary and even synergistic enhancement of vaccine-induced immune responses. Most combination adjuvants under investigation are chemically heterogeneous mixtures of depot adjuvants mixed with PRR agonists and suffer from batch-to-batch variability and poor chemical definition making investigation of mechanisms and safety a challenge. Our lab investigates self-assembling peptide nanofibers (PNFs) as vaccine adjuvants. A key advantage of PNFs over emulsion adjuvants is that the primary sequence of the self-associating peptide can be designed to control the physicochemical features of PNFs such as morphology, charge, chirality, or hydrophobicity, which are key contributors to adjuvant activity. Mechanistic insights into the mode of action indicates that unlike PAMPs, PNFs do not cause DC maturation but facilitate the release of DAMPs related to osmotic/oxidative stress. In this application, we propose to develop combination adjuvants composed of chemically defined DAMP-inducing peptide nanofibers (PNFs) and TLR2/NOD2 agonists. Our objectives are to understand how molecular mechanisms of DAMP-inducing PNFs and PRR agonists orchestrate innate immune signaling and induce responses that are complimentary, synergistic, or inhibitory for balancing immunogenicity with safety. In aim 1, we will examine the effect of PNFs with varying physicochemical properties and TLR2 or NOD2 agonist combinations on DC activation, DAMP release, and antigen presentation. In aim 2, using a design of experiments (DOE) approach, we will develop an optimal formulation with precisely controlled PNF-TLR2 and PNF-NOD2 combinations and determine the molecular mechanisms of innate immunity in DCs using various KO mouse models. In aim 3, we will validate the efficacy of PNF-TLR2-NOD2 combination adjuvants and investigate translational potential using human DCs. Outcomes of the proposed studies will advance our understanding of the molecular mechanisms that mediate innate immune responses to PNF-PRR agonist adjuvant combinations and will lead to new combinatorial- adjuvant platforms for combating infectious and non-infectious diseases with high translational potential.

项目摘要发现模式识别受体（PRR）的发现，包括Toll样受体（TLR）和点头样受体（NLR）导致研究了辅助配方中先天免疫的分子激动剂。新兴范式是仔细选择辅助组合可能会导致互补甚至疫苗诱导的免疫反应的协同增强。大多数组合佐剂研究是仓库佐剂与PRR激动剂混合的化学异质混合物并遭受的从批处理到批处理变异性和化学定义差，可以调查机制和安全性挑战。我们的实验室将自组装肽纳米纤维（PNF）作为疫苗佐剂。钥匙 PNF比乳液佐剂的优势是自我缔约肽的主要序列可以是旨在控制PNF的物理化学特征，例如形态学，电荷，手性或疏水性是辅助活动的关键因素。对行动方式的机械洞察力表明与小熊不同，PNF不会引起直流成熟，而是促进与渗透/氧化应激。在此应用中，我们建议开发由组成的组合佐剂化学定义的潮湿诱导肽纳米纤维（PNFS）和TLR2/NOD2激动剂。我们的目标是了解抑制PNF和PRR激动剂的分子机制如何编排先天免疫信号传导，并诱发互补，协同或抑制性的反应平衡免疫原性与安全性。在AIM 1中，我们将检查具有不同理化的PNF的效果在直流激活，潮湿释放和抗原表现上的性质和TLR2或NOD2激动剂组合。在AIM 2中，使用实验设计（DOE）方法，我们将精确地开发出最佳公式受控的PNF-TLR2和PNF-NOD2组合并确定先天的分子机制使用各种KO小鼠模型在DC中的免疫力。在AIM 3中，我们将验证PNF-TLR2-NOD2的功效组合佐剂并使用人类DC研究转化潜力。拟议研究的结果将提高我们对介导的分子机制的理解对PNF-PRR激动剂辅助组合的先天免疫反应，并将导致新的组合辅助平台，用于打击具有高转化潜力的传染病和非感染疾病。