Immunomodulatory Effects of Heterochiral Biomaterials

项目摘要 成功开发针对新出现病原体的亚单位疫苗的主要限制因素是 缺乏安全有效的免疫佐剂。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。基于肽的生物材料由于其生物相容性、折叠能力和生物相容性而具有吸引力。 特定的结构，易于合成，以及丰富的化学成分， 操纵以控制免疫调节特性。我们对自我发展感兴趣- 组装用于疫苗开发和免疫治疗的肽生物材料。 在本项目中，我们将开发新型自组装异手性肽生物材料， 自噬机制，用于针对蚊媒黄病毒的疫苗开发， West Nile（WNV）.在目标1中，我们将合成具有各种手性氨基酸模式的肽， 研究组装，形态，结构和散装材料的性能，如粘弹性和 蛋白水解稳定性在目标2中，我们将研究手性如何引起理化性质的变化， 肽生物材料的性质影响自噬、佐剂效力和抗体的机制 使用来自WNV的模型抗原或肽和蛋白质抗原的免疫应答。我们会把抗原 - 通过共价键或用肽水凝胶剪切变稀的来自病毒的肽或蛋白质结构域， 研究抗体应答、亲和力和中和能力。在目标3中，我们将测试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 日本脑炎抗原，其灭活的人疫苗可用作对照。 完成拟议的工作将整合生物材料，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，还针对其他 新出现的具有公共卫生重要性的黄病毒。

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.