Reverse Genomics of Anti-Protective Antigen Responses

抗保护性抗原反应的反向基因组学

• 批准号: 7695610
• 负责人: John Barker Harley
• 金额: $ 23.64万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7695610
• 关键词: Address; Adverse effects; Anthrax Vaccine Absorbed; Anthrax disease; Anthrax exposure; Antibodies; Antigens; Candidate Disease Gene; Data; Future; Genes; Genetic; Genome Scan; Genomics; Grant; Hand; Human; Immune response; Immunologics; Infection; Knowledge; Laboratories; Lead; Maps; Military Personnel; Molecular; Participant; Probability; Production; Resistance; Risk; Sampling; Screening procedure; Secure; Single Nucleotide Polymorphism; Stream; Time; Vaccinated; Vaccination; Vaccines; Veterinarians; X Chromosome; autosome; base; combat; genetic variant; positional cloning; response; tool; trait; vaccine development; vaccine efficacy

At the present time protection from anthrax exposure is largely based upon vaccination of those considered at risk, particularly including active duty military personnel in combat theaters, veterinarians in certain settings, and laboratory workers. The anti-Protective Antigen (PA) antibody level is widely considered the most easily accessible surrogate for a protective response from anthrax infection. We propose to apply the modern reverse genetics approach to this immune response in an effort to understand the genetic contributors to this vaccine response, in particular, and in the anticipation that genetic variants important in the response to anthrax will also be important in other successful vaccinations. To our knowledge modern reverse genetic tools have not been previously applied to develop a basic understanding of the genetic contribution to any vaccination, much less to anthrax. In three preliminary studies supported during the first grant cycle we have evaluated the relationship between the quantitative levels of anti-PA antibodies to 500,000 single nucleotide polymorphisms (SNPs) covering the autosomes and X chromosome in over 300 participants vaccinated with Anthrax Vaccine Absorbed (AVA). A number of candidate genes have been thereby identified, which warrant replication and fine mapping studies, the first of which is underway. We propose to expand the scope of the genome scan to 1,500,000 screening SNPs, and also to perform replication and fine mapping studies, to secure the participation of a total of 4000 vaccinated subjects, and to evaluate the genomics of the resulting genes. While it has taken a considerable effort to collect the samples necessary for this analysis, with samples now in hand, preliminary data available, and a now constant stream of new samples, the project is now ripe for substantial progress. The results of the project should identify many new genes important for the future development of vaccines and for understanding resistance to lethal anthrax.

目前，对炭疽接触的保护主要是基于对那些被考虑的人进行疫苗接种 处于危险之中，特别是包括战区的现役军事人员，某些兽医 环境和实验室工作人员。抗保护性抗原(PA)抗体水平被广泛认为是 最容易获得的替代品，对炭疽感染的保护性反应。我们建议将 现代反向遗传学方法对这种免疫反应进行了研究，以期了解 尤其是这种疫苗反应的贡献者，以及预期基因变异在 对炭疽病的反应在其他成功的疫苗接种中也将是重要的。据我们所知，现代 以前还没有应用反向遗传工具来建立对遗传的基本理解 对任何疫苗接种都有贡献，更不用说对炭疽病了。在第一次支持的三项初步研究中 Grant Cycle我们已经评估了抗PA抗体的定量水平与 覆盖常染色体和X染色体的500,000个单核苷酸多态(SNPs) 参与者接种了炭疽疫苗吸收(AVA)。一些候选基因已经被 由此确定，需要进行复制和精细绘图研究，第一项研究正在进行中。我们 建议将基因组扫描的范围扩大到1500,000个SNPs，并进行 复制和精细绘图研究，以确保总共4000名接种疫苗的受试者参与，并 评估产生的基因的基因组学。虽然已经花费了相当大的努力来收集样本 对于这一分析是必要的，样品现已在手，初步数据可用，现在是常量 随着新样品的涌现，该项目现在取得实质性进展的时机已经成熟。项目的结果应该是 识别许多对未来疫苗开发和了解耐药性很重要的新基因 致死的炭疽热。