Reverse Genomics of Anti-Protective Antigen Responses

目前，防止炭疽接触主要是基于对那些被认为是 处于危险之中，特别是包括在战区的现役军人， 设置和实验室工作人员。抗保护性抗原（PA）抗体水平被广泛认为是 最容易获得的炭疽感染保护性反应的替代品。我们建议采用 现代反向遗传学方法来研究这种免疫反应， 特别是对这种疫苗反应的贡献者，并且预计遗传变异对 对炭疽病的反应对其他成功的疫苗接种也很重要。据我们所知， 反向遗传工具以前没有应用于发展对遗传的基本理解， 对任何疫苗接种的贡献，更不用说炭疽了。在第一次会议期间支持的三项初步研究中， 我们已经评估了抗PA抗体的定量水平与 500，000个单核苷酸多态性（SNP），覆盖300多个常染色体和X染色体， 参与者接种了炭疽疫苗吸收（AVA）。一些候选基因已经被 从而确定，值得复制和精细绘图研究，其中第一个正在进行中。我们 我建议将基因组扫描的范围扩大到150万个SNPs， 复制和精细定位研究，以确保总共4000名接种受试者的参与，并 评估产生的基因的基因组学。虽然我们花了很大的努力来收集样本 这种分析是必要的，现在有样品，有初步数据，现在有一个常数。 新的样品流，该项目现在已经成熟，取得实质性进展。该项目的结果应 发现许多新基因，对未来疫苗的开发和了解耐药性很重要 致命的炭疽热

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.