Peptide Conformation Constrainment Technology and Novel Mucosal Adjuvants to

肽构象约束技术和新型粘膜佐剂

基本信息

批准号：
7701567
负责人：
THOMAS G BLANCHARD
金额：
$ 30.33万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-18 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7701567
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 Pan Genus 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 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

项目摘要

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.

疫苗接种是预防传染病的最成功和成本效益的方法之一。这然而，开发胃肠道感染的有效疫苗令人失望。这些疫苗的需求至关重要，因为由于肠道感染剂引起的腹泻疾病是全世界婴儿和幼儿的第二大领先感染原因。一些感染力引起腹泻疾病的药物包括轮状病毒，致病性大肠杆菌，志贺氏菌，spp。沙门氏菌属，隐孢子虫pan/urn，Entamoeba Histolictica和Vibrio Cholera。原因缺乏适合肠道病原体的疫苗是缺乏可以口服输送的有效佐剂疫苗以增加刺激免疫反应的效力。大多数实验性口服佐剂无效或维持一定程度的毒性。为了解决这个问题，我们建议夫妇从肠道病原体到安全稳定的辅助氧化铝的夫妇合成肽口服免疫的纳米颗粒。肽将以一种方式耦合到纳米颗粒保留其本地构象以优化免疫反应以识别本地病原。由于很少有肠道疾病和免疫力的小动物模型，我们将使用人类病原体幽门螺杆菌（H. Pylori）感染小鼠胃粘膜，我们将测试该技术 1）鉴定幽门螺杆菌CAGL上的表位，这些表位对于使用细菌与宿主细胞结合至关重要用人类细胞系阻断抗体，2）测试这些CAGL表位的能力，耦合到氧化铝纳米颗粒，在挑战前传递给小鼠时诱导保护性免疫，3）测试这些CAGL表位的能力，耦合到氧化铝纳米颗粒，诱导抗体这种阻止了由于幽门螺杆菌感染引起的致病性和致癌事件，4）评估抗体感染人类受试者的反应以确定这些阻断抗体是否由天然诱导感染以确定通过疫苗接种诱导这些抗体是否对人类患者。通过幽门螺杆菌模型中的感染，炎症或致癌作用减少与稳定的靶向肽表位相连的稳定的，靶向的肽表位将提供引人注目随后针对其他诱导其他肠道细菌感染的应用的证据重要的世界发病率和死亡率。