Recombination-quiescent genes & phylogenic validation of encoded vaccine targets

重组静止基因

基本信息

批准号：
8082726
负责人：
RICHARD GOLDSTEIN
金额：
$ 20.91万
依托单位：
BOSTON MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8082726
关键词：
Acute Address Amino Acid Sequence Animal Model Animals Antibodies Antigens Antimicrobial Resistance Bioinformatics Categories Child Childhood Code Collection Complement Activation Development Epitopes Funding Future Genes Genetic Recombination Genome Genomics Goals Immune Sera Infection Language Development Measures Morbidity - disease rate Operon Otitis Media Peptide Sequence Determination Pneumococcal Colonization Pneumococcal Infections Pneumococcal vaccine Prevention Protein S Proteins Research Project Grants Resistance Ribosomal RNA Serum Staging Streptococcus pneumoniae Surface Targeted Research Testing Vaccines Validation antimicrobial bactericide base env Gene Products global health hearing impairment innovation meetings mortality pathogen pressure protein expression public health relevance response skills vaccine candidate vaccine development

项目摘要

DESCRIPTION (provided by applicant): Invasive pneumococcal disease in children persists as a major cause of morbidity and mortality throughout the world despite introduction of the 7 valent capsular pneumococcal vaccine. Streptococcus pneumoniae is also the major cause of acute otitis media (AOM) which can result in hearing impairment or loss delaying the acquisition of language skills. Antimicrobial prescription for AOM is a major contributor to the rise of antimicrobial resistance. Diversifying selection-response to host immunological defenses has been a major impediment to the identification of conserved protein-based antipneumococcal vaccine candidates. A consequence of such selective pressure is the intra-species epitope variability typically found for exposed proteins on the outer surface of bacterial pathogens such as S. pneumoniae. This R21 proposal evaluates a bioinformatics-supported hypothesis for the identification of a previously unrecognized category of highly conserved, surface exposed proteins of S. pneumonia. The hypothesis is, that recombinationally quiescent 50 kb 'flanks' of ribosomal RNA operons (rrn) are a potential reservoir of genes coding for highly conserved, surface-exposed, antigenic envelope proteins (EnvP) that could be developed as potential vaccine candidates Specific aims are: (i) to utilize an innovative phylogenic strategy to screen rrn flank-encoding EnvP genes for extent of conservation across pneumococcal evolutionary diversity; (ii) clone/express/purify several such highly conserved EnvP for use as immunogens to generate polyclonal sera, and (iii) use the polyclonal antisera to test whether the EnvP meet basic criteria expected of a vaccine target: antibody accessibility of the EnvP across pneumococcal phylogenic diversity, and EnvP-elicited antibody functionality. R21-based validation of conserved, accessible and functional vaccine candidate antigens would provide the necessary preliminary results needed to support a future RO1 application focused on further EnvP vaccine development. PUBLIC HEALTH RELEVANCE: Invasive pneumococcal disease in children persists as a major cause of morbidity and mortality throughout the world despite introduction of the 7 valent capsular pneumococcal vaccine. Streptococcus pneumoniae is also the major cause of acute otitis media which can result in hearing impairment or loss, delaying the acquisition of language skills. Prevention of pneumococcal disease would have a major impact on global health and is necessary to achieve the WHO goals for reduction in childhood mortality.

描述（由申请人提供）：尽管引入了7个Valent囊囊肺炎球菌疫苗，但儿童的侵入性肺炎球菌疾病仍然是全球发病率和死亡率的主要原因。肺炎链球菌也是急性中耳炎（AOM）的主要原因，它可能导致听力障碍或损失延迟语言技能的获得。 AOM的抗菌处方是抗菌耐药性升高的主要因素。对宿主免疫防御的多样化选择反应多样化，这是鉴定基于蛋白质的抗脑癌疫苗候选物的主要障碍。这种选择性压力的结果是种类内表位变异性通常是针对细菌病原体（如肺炎链球菌）外表面上暴露的蛋白质发现的。该R21提案评估了生物信息学支持的假设，用于鉴定先前未认识到的高度保守的，表面暴露的肺炎链球菌的蛋白质。假设是，核糖体RNA操纵子（RRN）的重组静止50 kb“侧翼”是编码高度保守的，表面暴露的，表面暴露的，抗原蛋白（ENVP）的潜在储层，可以作为潜在疫苗的特定目标开发，以筛选特定于phencive phencies flanc，以筛选phencor的策略：（i（i），i（i）。跨肺炎球菌进化多样性的保护程度；（ii）克隆/express/净化几个这样的高度保守的环境，用于产生多克隆血清，（iii）使用多克隆抗血清测试ENVP是否符合疫苗目标的基本标准：ENVP跨肺炎球菌的抗体可访问性，以及肺炎球菌多样性多样性的抗生素和Euntp-euntp-entpody和Eutpodic eliditifipericationality and Eutpody和Eutpody elitiped-Eutpody和Eutpody elitiped-Eutpody和Eutpody Forkipicationalicatity。基于R21的保守，可访问和功能性疫苗候选抗原的验证将为支持未来的RO1应用所需的必要初步结果，以进一步的ENVP疫苗开发。公共卫生相关性：尽管引入了7个Valent胶囊肺炎球菌疫苗，但儿童的侵入性肺炎球菌疾病仍然是全球发病和死亡的主要原因。肺炎链球菌也是急性中耳炎的主要原因，可导致听力障碍或损失，从而延迟获得语言技能的获取。预防肺炎球菌疾病将对全球健康产生重大影响，对于实现WHO降低儿童死亡率的目标是必要的。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The diversity of the proline-rich domain of pneumococcal surface protein A (PspA): Potential relevance to a broad-spectrum vaccine.

DOI：
10.1016/j.vaccine.2018.08.045
发表时间：
2018-10-29
期刊：
Vaccine
影响因子：
5.5
作者：
Mukerji R;Hendrickson C;Genschmer KR;Park SS;Bouchet V;Goldstein R;Lefkowitz EJ;Briles DE
通讯作者：
Briles DE