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

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.

项目概要模式识别受体 (PRR) 的发现，包括 Toll 样受体 (TLR) 和 NOD 样受体受体（NLR）引发了对佐剂制剂中先天免疫分子激动剂的研究。一个新兴的范式是，仔细选择佐剂组合可以产生互补甚至均匀的效果。协同增强疫苗诱导的免疫反应。大多数组合佐剂研究发现，储库佐剂与 PRR 激动剂混合的化学异质混合物会受到影响由于批次间的差异和不良的化学定义，使得机制和安全性的调查成为可能挑战。我们的实验室研究自组装肽纳米纤维（PNF）作为疫苗佐剂。一把钥匙 PNF 相对于乳液佐剂的优点是自缔合肽的一级序列可以是旨在控制 PNF 的物理化学特征，例如形态、电荷、手性或疏水性，这是佐剂活性的关键因素。对作用模式的机制见解表明与 PAMP 不同，PNF 不会导致 DC 成熟，但会促进与以下相关的 DAMP 的释放：渗透/氧化应激。在此应用中，我们建议开发由以下组成的组合佐剂化学成分确定的 DAMP 诱导肽纳米纤维 (PNF) 和 TLR2/NOD2 激动剂。我们的目标是了解 DAMP 诱导 PNF 和 PRR 激动剂的分子机制协调先天免疫信号并诱导互补、协同或抑制的反应平衡免疫原性与安全性。在目标 1 中，我们将研究不同理化性质的 PNF 的影响特性以及 TLR2 或 NOD2 激动剂组合对 DC 激活、DAMP 释放和抗原呈递的影响。在目标 2 中，我们将使用实验设计 (DOE) 方法开发出一种精确的最佳配方控制PNF-TLR2和PNF-NOD2组合并确定先天性的分子机制使用各种 KO 小鼠模型获得 DC 免疫。在目标 3 中，我们将验证 PNF-TLR2-NOD2 的功效组合佐剂并使用人类树突状细胞研究转化潜力。拟议研究的结果将增进我们对介导的分子机制的理解 PNF-PRR 激动剂佐剂组合的先天免疫反应将导致新的组合- 具有高转化潜力的对抗传染性和非传染性疾病的佐剂平台。