Polymeric nanoassemblies for precise tuning of immune responses (Supplement for Equipment Purchase)

项目概要/摘要 炎症是一种强大的多因素宿主防御机制，旨在保护身体免受微生物的侵害。 损伤和组织损伤。因此，炎症不仅是维持体内平衡所必需的， 当监管机制出错时，它本身是有害的。异常的免疫激活在 人类疾病，并可能导致炎症（如败血症）、自身免疫和 过敏性疾病，对于这些疾病，解决潜在免疫问题的治疗选择有限 功能障碍我的研究计划的首要目标是阐明基本的和功能的 纳米颗粒设计与炎症背景下的生物学反应之间的关系 条件事实上，纳米颗粒可以被设计成具有固有的免疫调节特性， 通过非特异性或抗原特异性机制的炎症反应的程度。我们集团 在这两个领域取得了重大进展，我们已经证明，我们定制设计的纳米颗粒 可以减弱多种Toll样受体激动剂诱导的非特异性促炎反应， 不存在其它治疗剂。进一步证明了这些无载物纳米颗粒 将LPS诱导的内毒素血症致死小鼠模型的存活率提高至70%。肽或多肽的包封 将蛋白质抗原导入致耐受性纳米颗粒（tNP）中允许将抗原特异性递送至先天性免疫缺陷病毒（HIV）。 免疫细胞通过操纵先天免疫细胞抗原呈递给T细胞， 抗原特异性T细胞和疾病进展停止。tNP最近在第一阶段和第二阶段进行了评估， 治疗乳糜泻的临床试验取得成功。纳米颗粒的快速发展 临床实施的迫切需要机制研究，以阐明 基于纳米颗粒的免疫调节的基本原理。我们的目标是满足这一需求 通过利用我们在纳米颗粒设计和免疫工程方面的专业知识， 合成、纳米颗粒制剂和免疫学。在未来五年，我们将特别关注 纳米颗粒的物理和化学性质如何影响与以下相关的多种结果： 使用临床相关的体外和体内脓毒症、自身免疫和 过敏这些研究的结果将使我们能够建立一套设计规则， 免疫调节活性和纳米颗粒与免疫系统的相互作用，以指导开发 以及用于炎症和抗原特异性疾病干预的新型纳米颗粒的临床转化。 通过成功实现我们的计划，我们不仅将有助于我们对 纳米颗粒与免疫细胞相互作用并内化到免疫细胞中所必需的性质， 开发一套设计规则，管理基于纳米颗粒的免疫调节，这将立即 适合于未来转化应用的治疗价值。

PROJECT SUMMARY/ABSTRACT Inflammation is a powerful, multifactorial host defense mechanism intended to protect the body from microbial insult and tissue damage. As such, inflammation is not only essential to the maintenance of homeostasis but is on its own deleterious when regulatory mechanisms go awry. Aberrant immune activation is prominent in human diseases and can contribute to the development of inflammatory (e.g. sepsis), autoimmune, and allergic conditions for which there are limited therapeutic options available that address the underlying immune dysfunction. The overarching goal of my research program is to elucidate fundamental and functional relationships between nanoparticle designs and biological responses in the context of inflammatory conditions. Indeed, nanoparticles can be designed with inherent immunomodulatory properties that can limit the extent of the inflammatory response through non-specific or antigen-specific mechanisms. Our group has made significant strides in both of these areas where we have shown that our custom-designed nanoparticles could blunt non-specific proinflammatory responses induced by multiple Toll-like receptor agonists in the absence of additional therapeutic agents. It was further demonstrated that these cargo-less nanoparticles improved survival in lethal mouse models of LPS-induced endotoxemia to 70%. Encapsulation of peptide or protein antigens into tolerogenic nanoparticles (tNPs) allows for the specific delivery of antigens to innate immune cells. Through manipulation of innate immune cell antigen presentation to T cells, the activation of antigen-specific T cells and disease progression was halted. tNPs were recently evaluated in a Phase I and II clinical trial for the treatment of celiac disease with success. The rapid progression of nanoparticles towards clinical implementation highlights the urgent need for mechanistic studies to elucidate the underlying principles that govern nanoparticle-based immunomodulation. We aim to address this need by capitalizing on our expertise in nanoparticle design and immune engineering, which includes polymer synthesis, nanoparticle formulation, and immunology. Over the next five years, we will specifically focus on how the physical and chemical properties of nanoparticles affect multiple outcomes associated with inflammatory responses using clinically-relevant in vitro and in vivo models of sepsis, autoimmunity, and allergy. The outcomes of these studies will enable us to establish a set of design rules that govern the immunomodulatory activity and interactions of nanoparticles and the immune system to guide the development and clinical translation of novel nanoparticles for inflammation and antigen-specific disease intervention. Through successful realization of our program, we will not only contribute to our understanding of the properties that are necessary for nanoparticles to interact with and internalize into immune cells but also develop a set of design rules that govern nanoparticle-based immunomodulation, which will have immediate therapeutic value suitable for future translational applications.