Programming innate immune responses using glycomimetic macromolecular complexes

非技术摘要：先天免疫是免疫系统的一部分，它识别病原体（如细菌、病毒和真菌）中使用的特定化学模式，但不常见于我们的细胞和哺乳动物细胞。这些模式包括双链RNA，某些类型的DNA和称为脂多糖（LPS）的糖基分子。检测到这些分子模式是入侵的潜在信号，并引发防御反应。人们已经发现，某些不应该被先天免疫系统检测到的分子实际上可以通过简单地与DNA和RNA形成有组织的结构来刺激并极大地放大这种先天免疫反应。这是完全出乎意料的，可能会改变对分子识别的基本理解。这项拟议研究的目标是了解控制这些现象的规则，设计和测试新的合成分子，可以模拟这种免疫系统的放大，并设计新的合成分子，可以关闭这一过程。从这项研究中获得的基本知识将广泛适用。潜在的长期成果包括用于更好地控制免疫系统的生物材料和用于检测特定化学物质的更好的传感器。这项工作将在若干方面扩大参与。拟议工作的多学科性质将为这一新兴领域提供充足的教育机会。本文的研究课题有利于学术和产业就业的培训。研究实习将通过代表性不足的本科生和退伍军人外展项目提供。该结果将被纳入pi的高级本科/研究生课程。技术摘要：先天免疫是一种非特异性防御机制，具有哺乳动物细胞不具有的特异性化学识别基序。这些病原体相关分子模式（PAMPs）的检测表明外来细胞的存在，并引发炎症反应。toll样受体（TLRs）能够识别特定的免疫配体类别：dsRNA由TLR3识别，而TLR9识别致病性dsDNA；两者都激活信号转导通路，导致促炎细胞因子的产生和用于病原体防御的抗菌肽（AMPs）的上调。他的研究小组最近对TLR9和TLR3激活的研究揭示了免疫调节的一个新的、意想不到的物理基础。具有特定结构特征的分子可以与免疫配体共同组装成纳米晶体复合物，从而大幅上调免疫反应：这些复合物的免疫配体的空间周期性呈现通过与多个tlr的插入结合驱动扩增。这代表了分子识别中心范式的重要概括。先天免疫受体不仅可以识别单个配体分子上的PAMPs，还可以识别配体的纳米晶体排列。本文的目的是了解这种新型的分子识别，设计化学同源的、具有结构特征的自组装dsDNA复合物家族，并定量控制下游免疫刺激。潜在的长期成果包括用于更好地控制免疫系统的生物材料和用于检测特定化学物质的更好的传感器。拟议工作的多学科性质将为这一新兴领域提供充足的教育机会。本文的研究课题有利于学术和产业就业的培训。研究实习将通过代表性不足的本科生和退伍军人外展项目提供。该结果将被纳入pi的高级本科/研究生课程。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Non-Technical abstract: Innate immunity is a part of the immune system that recognizes specific chemical patterns used in pathogens (ex: bacteria, viruses, and fungi) but not common to our cells and mammalian cells. These patterns include double-stranded RNA, certain types of DNA and sugar-based molecules known as lipopolysaccharides (LPS). Detection of these molecular patterns is a potential sign of invasion, and trigger defensive responses. It has been discovered that certain molecules that are not supposed to be detected by the innate immune system can in fact stimulate and greatly amplify this innate immune response, by simply forming organized structures with DNA and with RNA. This is completely unexpected, and can potentially revise fundamental understanding of molecular recognition. The goal of this proposed research is to understand the rules governing these phenomena, and design and test new synthetic molecules that can mimic this immune system amplification, and to design new synthetic molecules that can turn off this process. The basic knowledge gained as a result of this research will be broadly enabling. Potential long term outcomes include biomaterials for better control of the immune system and better sensors for detection of specific chemicals. This work will broaden participation in a number of ways. The multi-disciplinary nature of the proposed work will provide ample educational opportunities in this emerging field. The research topics here are conducive to training for academic and industrial employment. Research internships will be provided through underrepresented undergraduate and veteran outreach programs. Results from this will be incorporated into the PIs' advanced undergraduate/graduate classes. Technical abstract:Innate immunity is a non-specific defense mechanism against pathogens bearing specific chemical recognition motifs not common to mammalian cells. Detection of these pathogen-associated molecular patterns (PAMPs) signals the presence of foreign cells, and trigger inflammatory responses. Toll-like receptors (TLRs) are capable of recognizing specific immune ligand classes: dsRNA is recognized by TLR3, while TLR9 recognizes pathogenic dsDNA; both activate signal transduction pathways that lead to the production of pro-inflammatory cytokines and upregulation of antimicrobial peptides (AMPs) for pathogen defense. Recent work from his research group on TLR9 and TLR3 activation reveal a new, unexpected physical basis for immunomodulation. Molecules with specific structural characteristics can co-assemble with immune ligands into nanocrystalline complexes that drastically upregulate immune responses: The spatially-periodic presentation of immune ligands by these complexes drive amplification via intercalative binding with multiple TLRs. This represents a significant generalization of the central paradigm in molecular recognition. Innate immune receptors can recognize not just PAMPs on single ligand molecules, but also recognize nanocrystalline arrangements of ligands. Here, the aim is to understand this new type of molecular recognition, and design chemically-cognate, structurally-characterized families of self-assembled dsDNA complexes and quantitatively control downstream immune stimulation. Potential long term outcomes include biomaterials for better control of the immune system and better sensors for detection of specific chemicals. The multi-disciplinary nature of the proposed work will provide ample educational opportunities in this emerging field. The research topics here are conducive to training for academic and industrial employment. Research internships will be provided through underrepresented undergraduate and veteran outreach programs. Results from this will be incorporated into the PIs' advanced undergraduate/graduate classes.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.