Peptide Conformation Constrainment Technology and Novel Mucosal Adjuvants to

肽构象约束技术和新型粘膜佐剂

• 批准号: 8378490
• 负责人: THOMAS G BLANCHARD
• 金额: $ 22.6万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8378490
• 关键词: Active Sites; Address; Adjuvant; Aluminum Hydroxide; Aluminum Oxide; Amino Acid Sequence; Animal Model; Animals; Antibodies; Antibody Formation; Avidity; Bacteria; Bacterial Infections; Binding; Biological Assay; Biopsy; Blocking Antibodies; Cancerous; Cause of Death; Cell Culture Techniques; Cells; Child; Clinical; Coculture Techniques; Communicable Diseases; Coupled; Cryptosporidium; Cryptosporidium parvum; Development; Diagnosis; Diarrhea; Disease; Disease Progression; Drug Formulations; Dysentery; Entamoeba histolytica; Enteral; Epithelial Cells; Epitopes; Evaluation; Event; Failure to Thrive; Gastric mucosa; Gastrointestinal tract structure; Goals; Helicobacter Infections; Helicobacter pylori; Histologic; Human; Human Cell Line; Immune response; Immunity; Immunization; Immunologics; In Vitro; Infant; Infection; Infectious Agent; Inflammation; Inflammatory; Integrins; Lamina Propria; Lead; Lesion; Leucocytic infiltrate; Link; Malnutrition; Measures; Modeling; Molecular Conformation; Morbidity - disease rate; Mouse Cell Line; Mucosal Immunity; Mucous Membrane; Mus; Oncogene Proteins; Oral; Pathogenesis; Patients; Peptide Conformation; Peptide Vaccines; Peptides; Premalignant; Production; Proteins; Rotavirus; Salmonella; Serum; Severities; Shigella; Signal Transduction; Stomach; Stomach Diseases; Subunit Vaccines; System; Technology; Testing; Therapeutic; Toxic effect; Vaccination; Vaccines; Vibrio cholerae; Viral; carcinogenesis; cost effective; enteric pathogen; human subject; in vivo; malignant stomach neoplasm; microbial; microbial colonization; microorganism antigen; mortality; mouse model; nanoparticle; new technology; pathogen; pathogenic Escherichia coli; prevent; prophylactic; response; success; synthetic peptide; vaccine development; vaccine efficacy

Vaccination is one of the most successful and cost-effective ways of preventing infectious disease. The development of effective vaccines for infections of the gastrointestinal tract however has been disappointing. The need for these vaccines is crucial since diarrheal diseases due to infectious agents of the gut are the second leading infectious cause of death in infants and young children world wide. Some of the Infectious agents that cause diarrheal diseases include rotavirus, pathogenic Escherichia coli, Shigella spp., Salmonella spp., Cryptosporidium pan/urn, Entamoeba histolytica, and Vibrio cholera. The reason for the lack of suitable vaccines for enteric pathogens is the lack of an effective adjuvant that can be delivered orally with the vaccine to increase its potency at stimulating an immune response. Most experimental oral adjuvants are ineffective or maintain some degree of toxicity. To address this problem, we propose to couple synthetic peptides from enteric pathogens to a safe and stable adjuvant, aluminum oxide nanoparticles for oral immunization. The peptides will be coupled to the nanoparticles in a way that preserves their native conformation in order to optimize the immune response to recognize the native pathogen. Since very few small animal models of enteric disease and immunity exist, we will use the human pathogen Helicobacter pylori (H. pylori) to infect the mouse gastric mucosa and we will test this technology by 1) Identifying epitopes on H. pylori CagL that are crucial for binding of the bacteria to host cells using an antibody blocking assay with human cell lines, 2) Testing the ability of those CagL epitopes, coupled to aluminum oxide nanoparticles, to induce protective immunity when delivered to mice prior to challenge, 3) Testing the ability of those CagL epitopes, coupled to aluminum oxide nanoparticles, to induce antibodies that block pathogenic and carcinogenic events due to H. pylori infection, and 4) Evaluating the antibody response of infected human subjects to determine if these blocking antibodies are induced by natural infection in order to determine if the induction of these antibodies by vaccination would be beneficial to human patients. A reduction of infection, inflammation, or carcinogenesis in the H. pylori model by immunization with stable, targeted peptide epitopes coupled to nanoparticles would provide compelling evidence for subsequent applications against other enteric bacterial infections in humans that induce significant world wide morbidity and mortality.

接种疫苗是预防传染病最成功和最具成本效益的方法之一。的 然而，用于胃肠道感染的有效疫苗的开发令人失望。 对这些疫苗的需求是至关重要的，因为由于肠道感染因子引起的肠道疾病是 世界范围内婴儿和幼儿死亡的第二大传染性原因。一些传染病 引起腹泻病的病原体包括轮状病毒，致病性大肠杆菌，志贺氏菌属， 沙门氏菌属，隐孢子虫、溶组织内阿米巴和霍乱弧菌。的原因 缺乏用于肠道病原体的合适疫苗是缺乏可口服递送的有效佐剂 以增加其刺激免疫反应的效力。大多数实验性口腔 佐剂是无效的或保持一定程度的毒性。为解决这个问题，我们建议 将来自肠道病原体的合成肽与安全稳定的佐剂氧化铝偶联 用于口服免疫的纳米颗粒。肽将以一种方式与纳米颗粒偶联， 保持它们的天然构象，以优化免疫应答， 病原体由于存在很少的肠道疾病和免疫的小动物模型，我们将使用人 病原体幽门螺杆菌（H. pylori）感染小鼠胃粘膜，我们将测试这项技术 通过1）鉴定H. pylori CagL，其对于细菌与宿主细胞的结合至关重要， 用人细胞系的抗体阻断测定，2）测试那些CagL表位的能力， 氧化铝纳米颗粒，当在攻击前递送至小鼠时诱导保护性免疫，3） 测试这些CagL表位与氧化铝纳米颗粒偶联诱导抗体的能力 阻断H.幽门螺杆菌感染，以及4）评估抗体 感染的人类受试者的反应，以确定这些阻断抗体是否是由天然抗体诱导的。 感染，以确定通过接种疫苗诱导这些抗体是否有益于 人类病人减少感染、炎症或H.幽门螺杆菌模型 用与纳米颗粒偶联的稳定的靶向肽表位进行免疫将提供令人信服的 用于后续应用以对抗人类其他肠道细菌感染的证据， 世界范围内发病率和死亡率都很高。