CAREER: Rational design of a biomimetic nanomaterial library to probe mechanisms behind virus-induced immunopathology

职业：合理设计仿生纳米材料库以探究病毒诱导的免疫病理学背后的机制

• 批准号: 1453576
• 负责人: Evan Scott
• 金额: $ 50.38万
• 依托单位: Northwestern University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-15 至 2021-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1453576&HistoricalAwards=false
• 关键词: CAREER; Rational; design; biomimetic; nanomaterial

PI: Scott, Evan A.Proposal Number: 1453576Viruses are intricate nanoscale structures that have evolved diverse strategies of influencing the immune system to evade detection and prolong residence within their hosts. The resulting virus-related pathophysiology is accompanied by well-intended inflammatory immune responses aimed at rectifying a disrupted homeostasis. The morphology, surface chemistry, and cellular targets of viruses directs this inflammation, which in many instances becomes dysregulated, resulting in a range of pathologies that can be more harmful than the original viral infection itself. Understanding the specific inflammatory triggers that can induce a particular immunological response is therefore essential to the identification and treatment of virus-induced pathologies as well as impact a broad range of inflammation-driven disease states including atherosclerosis and even seasonal allergies. Unfortunately, the specific mechanisms that are responsible for such harmful immune dysregulations are often prohibitively complex and difficult to isolate. Recent advances in biomedical engineering (BME) and nanotechnology now permit unprecedented control over the physical and chemical properties of synthetic nanostructures, which can be designed to mimic the mechanisms of infection utilized by nanoscale pathogens such as viruses. The research objective of this proposal is therefore to engineer virus-mimicking nanostructures that will serve as tools to investigate specific hypotheses of how viruses can generate dysregulated immune responses. As engineering approaches to immunological questions become more commonplace, future students and researchers interested in highly specialized areas of immunology and virology must be encouraged to pursue careers in the field of BME. The educational objective of this proposal therefore implements a multi-pronged high school BME program that exposes students, as well as their parents, to the diverse opportunities made accessible by a career in BME. This proposal aims to expand BME into new specialized fields of biological science by directly demonstrating the benefits of engineering-based techniques and principles.A key need in the study of viral immunopathology is a customizable, in situ method to probe how specific viral structures, surface chemistries, and biodistributions contribute to virus-induced dysregulation of the immune system. The PI will rationally design a library of virus-mimicking polymeric nanocarriers (NCs) to investigate the basic biochemical and cellular mechanisms that trigger the model immunodysregulatory disorder hemophagocytic lymphohistiocytosis (HLH). HLH can be controllably induced in several mouse models following infection by the lymphocytic choriomeningitic virus (LCMV). Since the polymers are inert and do not elicit inflammatory responses, the NCs can be considered "blank slates" in which a diverse range of molecules and immunostimulants will be incorporated for controlled transport to and activation of specific immune cells. The essential inflammatory mechanisms that induce HLH are poorly understood, and so this system will be simplified by dividing the various inflammatory components within LCMV, such as its glycoprotein envelope or RNA, into separate NCs that mimic the biodistribution and mechanisms of intracellular degradation of the virus. NCs are assembled from block copolymers, and can be engineered into vesicular and filamentous nanostructures, which respectively target diverse and restricted subsets of inflammatory immune cells. Vesicles will probe hypothesized biochemical mechanisms responsible for HLH by inducing controlled systemic cytokine expression and effector T cell activation. The filaments will investigate the specific cellular role of plasmacytoid dendritic cells, which are an inflammatory immune cell population essential to immune responses against LCMV. Through the use of controlled synthetically induced infections, the key LCMV-related inflammatory mechanisms or combinations thereof responsible for HLH will be identified. This work will demonstrate the use of rationally designed nanomaterials to enhance the understanding of how specific inflammatory triggers contribute to immunopathology. Furthermore, data gathered in these studies will provide insight into essential design criteria required for eliciting specific and controlled immunological responses.

PI：Scott，Evan A。提案编号：1453576 病毒是复杂的纳米级结构，它们已经进化出多种影响免疫系统的策略，以逃避检测并延长在宿主体内的停留时间。由此产生的与病毒相关的病理生理学伴随着旨在纠正被破坏的体内平衡的良好炎症免疫反应。病毒的形态、表面化学和细胞靶标引导这种炎症，在许多情况下炎症会失调，导致一系列比原始病毒感染本身更有害的病理。 因此，了解可诱导特定免疫反应的特定炎症触发因素对于识别和治疗病毒引起的病理以及影响广泛的炎症驱动的疾病状态（包括动脉粥样硬化，甚至季节性过敏）至关重要。 不幸的是，导致这种有害的免疫失调的具体机制通常非常复杂且难以分离。 生物医学工程 (BME) 和纳米技术的最新进展现在可以对合成纳米结构的物理和化学特性进行前所未有的控制，可以设计模拟病毒等纳米级病原体所利用的感染机制。 因此，该提案的研究目标是设计模仿病毒的纳米结构，将其作为研究病毒如何产生失调的免疫反应的具体假设的工具。随着免疫学问题的工程方法变得越来越普遍，必须鼓励未来对免疫学和病毒学高度专业领域感兴趣的学生和研究人员在 BME 领域从事职业。 因此，该提案的教育目标是实施多管齐下的高中 BME 计划，让学生及其家长获得 BME 职业带来的多样化机会。该提案旨在通过直接展示基于工程的技术和原理的优势，将 BME 扩展到生物科学的新专业领域。病毒免疫病理学研究的一个关键需求是一种可定制的原位方法，以探测特定病毒结构、表面化学和生物分布如何导致病毒引起的免疫系统失调。 PI将合理设计一个模拟病毒的聚合物纳米载体（NC）库，以研究触发模型免疫失调疾病噬血细胞性淋巴组织细胞增多症（HLH）的基本生化和细胞机制。 淋巴细胞脉络膜脑膜炎病毒 (LCMV) 感染后的几种小鼠模型可以可控地诱导 HLH。 由于聚合物是惰性的并且不会引起炎症反应，因此NC可以被认为是“白板”，其中将掺入多种分子和免疫刺激剂，以受控运输到特定免疫细胞并激活特定免疫细胞。 诱导 HLH 的基本炎症机制尚不清楚，因此该系统将通过将 LCMV 内的各种炎症成分（例如其糖蛋白包膜或 RNA）划分为模拟病毒生物分布和细胞内降解机制的单独 NC 来简化。 NC 由嵌段共聚物组装而成，可以被设计成囊泡和丝状纳米结构，分别针对炎症免疫细胞的多种和有限子集。 囊泡将通过诱导受控的全身细胞因子表达和效应 T 细胞激活来探索 HLH 的假设生化机制。 这些细丝将研究浆细胞样树突状细胞的特定细胞作用，浆细胞样树突状细胞是针对 LCMV 免疫反应所必需的炎症免疫细胞群。 通过使用受控的合成诱导感染，将确定导致 HLH 的关键 LCMV 相关炎症机制或其组合。 这项工作将展示合理设计的纳米材料的使用，以增强对特定炎症触发因素如何影响免疫病理学的理解。此外，这些研究中收集的数据将有助于深入了解引发特异性和受控免疫反应所需的基本设计标准。