IRON REGULATION & VIRULENCE--MYCOBACTERIUM TUBERCULOSIS

该候选人正在完成为期三年的传染病奖学金，并在过去两年中致力于结核病的基础科学研究。 特别是，候选人对研究结核病的基因调控感兴趣，以阐明可能成为重要药物和疫苗靶点的毒力基因和蛋白质抗原。 通过在该补助金下进行的研究，候选人希望在学术医疗机构担任初级教员，并继续使用分子生物学技术研究结核病的发病机制。 与白喉铁依赖调节子的领导者John Murphy博士和开发了可复制的结核病感染巨噬细胞模型的Richard银博士合作，候选人将拥有成功完成该项目所需的协作资源。 申办者William Bishai博士在分枝杆菌基因调控和结核病发病机制方面具有成熟的专业知识。 为了补充她的研究，候选人将参加每周约3小时的传染病和结核病相关会议。 她还计划在医学院和公共卫生学院学习分子生物学、结核病、疫苗开发和免疫学等课程。在抗生素耐药性和艾滋病毒感染的推动下，全球结核病感染的负担是惊人的。 新的抗菌剂和疫苗的毒力机制和蛋白抗原的阐明已经走到了最前沿。 铁是大多数生物体生存的必需营养素，在多种重要传染病病原体的毒力中发挥着核心作用。 使用棒状杆菌，铁依赖性DtxR调节子作为模型，候选人将研究分枝杆菌同源物，ideR及其调节子。 初步结果表明，铁的非依赖性，棒状杆菌DtxR突变体的超阻遏物减弱结核分枝杆菌在小鼠模型中的毒力。 已经构建了分枝杆菌ideR的类似突变体，并将使用凝胶迁移试验进行体外测试，以及在小鼠和巨噬细胞模型中进行体内测试。 利用DtxR/IdeR“铁盒”，回文DNA结合序列中存在的所有DtxR调控的基因，其他感兴趣的基因已被确定在计算机上，并将进行检查。 这种铁依赖性IdeR调节子的阐明可能导致毒力决定因素的鉴定，以及用于疫苗和治疗的新抗原。

The candidate is completing a three year infectious disease fellowship and has devoted the last 2 years to basic science research in tuberculosis. In particular, the candidate is interested in studying gene regulation in tuberculosis to elucidate virulence genes and protein antigens which may make important drug and vaccine targets. Through the research conducted under this grant, the candidate would like to establish herself as a junior faculty member at an academic medical institution and continue to pursue tuberculosis disease pathogenesis using molecular biologic techniques. In collaboration with Dr. John Murphy, a leader in iron-dependent regulons in diphtheria, and Dr. Richard Silver, who has developed a reproducible macrophage model of tuberculosis infection, the candidate will have the collaborative resources necessary for the successful completion of this project. The sponsor, Dr. William Bishai, has well-established expertise in mycobacterial gene regulation and tuberculosis disease pathogenesis. To complement her research, the candidate will attend approximately 3 hours per week of infectious disease and TB-related conferences. She also plans to take courses in molecular biology, tuberculosis, vaccine development, and immunology in the School of Medicine and the School of Public Health and Hygiene. Fueled by antibiotic resistance and HIV infection, the global burden of tuberculosis infection is staggering. The elucidation of virulence mechanisms and protein antigens for new antimicrobials and vaccines has moved to the forefront. Iron is an essential nutrient for the survival of most organisms and has played a central role in the virulence of multiple important infectious disease pathogens. Using the corynebacterial, iron- dependent DtxR regulon as a model, the candidate will study the mycobacterial homologue, ideR and its regulon. Preliminary results have shown that an iron-independent, corynebacterial DtxR mutant hyperrepressor attenuates Mycobacterium tuberculosis virulence in a murine model. A similar mutant of the mycobacterial ideR has been constructed and will be tested in vitro using a gel-shift assay, and in vivo in a murine and macrophage models. Taking advantage of the DtxR/IdeR "iron box", a palindromic DNA binding sequence present in all DtxR-regulated genes, other genes of interest have been identified in silico and will be examined. Elucidation of this iron-dependent IdeR regulon may lead to the identification of virulence determinants, and novel antigens for vaccines and therapeutics.