Immunomodulatory Effects of Heterochiral Biomaterials

项目总结 成功开发针对新病原体的亚单位疫苗的一个主要限制因素是 缺乏有效和安全的免疫佐剂。生物材料免疫工程是一个新兴的领域， 为开发针对传染病、癌症、 和自身免疫性疾病。基于多肽的生物材料因其生物相容性、折叠能力而备受关注 转化为特定的结构，易于合成，以及初级序列可以具有丰富的化学成分 操纵以控制免疫调节特性。我们对自我发展很感兴趣 组装多肽生物材料，用于疫苗开发和免疫治疗。 在目前的项目中，我们将开发新型的自组装异手性多肽生物材料 自噬机制在蚊媒黄病毒疫苗开发中的应用 西尼罗河(西尼罗州)。在目标1中，我们将合成具有不同模式的手性氨基酸和 研究组装、形态、结构和大块材料特性，如粘弹性和 蛋白质分解稳定性。在目标2中，我们将研究手性如何引起物理化学的变化。 多肽生物材料的性质影响自噬、佐剂效力和抗体的机制 使用模型抗原或来自西尼罗河病毒的多肽和蛋白质抗原的应答。我们会提供抗原性 通过共价键或与多肽水凝胶剪切变稀的病毒多肽或蛋白质结构域以及 研究抗体反应、亲和力和中和能力。在目标3中，我们将测试针对西尼罗河病毒的保护 在小鼠模型中的挑战和神经侵袭，并使用 可用灭活人用疫苗作为对照的日本脑炎抗原。 拟议工作的完成将整合生物材料、化学、免疫学和病毒学领域 用于开发基于生物材料的免疫平台，不仅针对西尼罗河病毒，而且还针对其他 对公共卫生具有重要意义的新出现的黄病毒。

PROJECT SUMMARY A major limiting factor to the development of successful subunit vaccines against emerging pathogens is the lack of effective and safe immune adjuvants. Biomaterials immunoengineering is a nascent field that is generating promising avenues for the development of subunit vaccines against infectious diseases, cancers, and autoimmune disorders. Peptide based biomaterials are attractive due to their biocompatibility, ability to fold into specific structures, ease of synthesis, and the rich chemistry with which the primary sequence can be manipulated to control the immunomodulatory properties. We are interested in the development of self- assembling peptide biomaterials for applications in vaccine development and immunotherapies. In the current project, we will develop novel self-assembling heterochiral peptide biomaterials that engage mechanisms of autophagy for applications in vaccine development against mosquito-borne flaviviruses such as West Nile (WNV). In aim 1, we will synthesize peptides with various patterns of chiral amino acids and investigate the assembly, morphology, structure, and bulk material properties such as viscoelasticity and proteolytic stability. In Aim 2, we will investigate how chirality-induced changes in the physicochemical properties of peptide biomaterials impact mechanisms of autophagy, adjuvant potency, and antibody responses using model antigens or peptide and protein antigens derived from WNV. We will deliver antigenic peptides or protein domains from viruses via covalent linkage or shear-thinned with peptide hydrogels and investigate antibody responses, affinity, and neutralization capacity. In aim 3, we will test protection from WNV challenge and neuroinvasion in mouse models and assess translational capacity of peptide biomaterials using Japanese encephalitis antigens for which inactivated human vaccines are available to serve as controls. Completion of the proposed work will integrate the fields of biomaterials, chemistry, immunology, and virology for the development of biomaterials-based immunization platforms against not only WNV, but also other emerging flaviviruses of public health importance.