Novel Therapies Targeting Mitochondrial Pathways in Lung Epithelial Response to S. Pneumoniae Infection

这份CDA-2申请书提出了一个为期5年的培训计划，以发展尼古拉斯·莫里斯博士的职业生涯 他研究了肺炎链球菌的致病机制，重点是这种相互作用是如何 细菌毒力因子与宿主线粒体DNA氧化损伤和修复之间的关系 对肺炎球菌感染的先天免疫反应。他的主要导师Ruxana Sadikot博士是一位 国际公认的宿主防御细菌病原体领域的专家。他的导师团队 包括亚特兰大退伍军人管理局和埃默里大学的其他高级调查人员，他们在以下方面相互补充 为莫里斯博士的职业发展做出贡献的专业知识。此外，莫里斯博士还将受益于 亚特兰大退伍军人医学中心和埃默里大学拥有良好的培训环境，拥有成熟的赛道 发展年轻调查人员职业生涯的成功记录。莫里斯博士之前发表的研究 铜绿假单胞菌主要致病因子的鉴定 宿主上皮细胞线粒体生物能功能和线粒体功能减弱引起的免疫 生物发生学。他证明了增强线粒体的遗传和药物策略 生物发生可促进上皮性宿主防御。基于他研究线粒体生物发生的工作， 莫里斯博士开始研究另一个线粒体质量控制过程，即线粒体DNA 修理。他还开始关注肺炎链球菌，因为它对人类健康构成了重大威胁。 退伍军人。初步研究确认了肺炎链球菌诱导氧化的新发现 宿主上皮细胞线粒体DNA损伤和DNA修复酶OGG1表达减弱 细胞。更多的数据表明，这一途径可能会对上皮性宿主产生重大影响 对肺炎球菌感染的反应。这项工作导致了肺炎球菌毒力因子的假设 如肺炎溶血素，一种依赖胆固醇细胞溶血素，通过氧化线粒体损害宿主防御 DNA损伤，但靶向增强线粒体DNA修复可以改善细胞功能障碍和 改善宿主对肺炎球菌感染的反应。这项建议包括三个目标。首先， 肺炎链球菌毒力因子诱导线粒体DNA氧化损伤和 宿主上皮细胞中OGG1表达的减弱将被证实。第二，活性氧的作用 上皮性宿主中物种介导的线粒体损伤和OGG1介导的线粒体DNA修复 将定义对肺炎链球菌的反应。第三，在临床前翻译研究中，新的治疗方法 针对线粒体OGG1的策略将在肺炎球菌肺炎的体内模型中进行测试，以 确定加强线粒体DNA修复是否反映了肺炎链球菌的有效治疗策略 感染。这些研究将提供关于宿主-肺炎球菌相互作用的新见解 有可能转化为人类临床研究。此外，实现这些目标所需的培训将 为莫里斯博士提供必要的技能，使其成为一名在 微生物学、线粒体生物学、肺天然免疫和 氧化还原生物学。在被授予退伍军人事务部VISN7研究发展奖后，莫里斯博士成为了一名员工 亚特兰大退伍军人医学中心医生，并加入埃默里大学医学院教职。他 正处于他职业发展的关键阶段，CDA-2的支持将使他能够实现他的目标 成为一名独立资助的内科科学家，目标是改善易感人群的健康 退伍军人面临感染威胁生命的风险。

This CDA-2 application proposes a 5-year training program to develop the career of Dr. Nicholas Maurice as he investigates mechanisms of Streptococcus pneumoniae pathogenicity with a focus on how the interaction between bacterial virulence factors and host mitochondrial oxidative DNA damage and repair modulates the innate immune response to pneumococcal infection. His primary mentor, Dr. Ruxana Sadikot, is an internationally-recognized expert in the field of host defense against bacterial pathogens. His mentorship team includes other senior investigators at the Atlanta VA and Emory University with complementary areas of expertise that will contribute to Dr. Maurice’s career development. In addition, Dr. Maurice will benefit from an excellent training environment at the Atlanta VA Medical Center and Emory University with a proven track record of success developing the careers of young investigators. Previous published research by Dr. Maurice identified key virulence factors of the bacterial pathogen, Pseudomonas aeruginosa, that impair innate immunity through attenuation of host epithelial cell mitochondrial bioenergetic function and mitochondrial biogenesis. He demonstrated that genetic and pharmacologic strategies that enhanced mitochondrial biogenesis could promote epithelial host defense. Based on his work investigating mitochondrial biogenesis, Dr. Maurice began investigating another mitochondrial quality control process namely mitochondrial DNA repair. He also began focusing on the bacteria S. pneumoniae given the significant health threat it poses to the veteran population. Preliminary research has identified the novel finding that S. pneumoniae induces oxidative mitochondrial DNA damage and attenuates expression of the DNA repair enzyme, OGG1, in host epithelial cells. Additional data suggest that this pathway may have significant consequences on the epithelial host response to pneumococcal infection. This work has led to the hypothesis that pneumococcal virulence factors such as pneumolysin, a cholesterol-dependent cytolysin, impair host defense through oxidative mitochondrial DNA damage, but targeted enhancement of mitochondrial DNA repair can ameliorate cellular dysfunction and improve the host response to pneumococcal infection. This proposal encompasses three aims. First, the pneumococcal virulence factors responsible for the induction of oxidative mitochondrial DNA injury and attenuation of OGG1 expression in host epithelial cells will be identified. Second, the role of reactive oxygen species-mediated mitochondrial damage and OGG1-mediated mitochondrial DNA repair in the epithelial host response to S. pneumoniae will be defined. Third, in pre-clinical translational studies, novel therapeutic strategies targeting mitochondrial OGG1 will be tested in an in vivo model of pneumococcal pneumonia to determine if enhancing mitochondrial DNA repair reflects an efficacious treatment strategy for S. pneumoniae infection. These studies will provide novel insights regarding host-pneumococcal interactions that have the potential for translation into human clinical studies. Further, the training necessary to achieve these aims will provide Dr. Maurice the skills necessary to develop into an independent physician scientist working at the intersection of multidisciplinary fields of microbiology, mitochondrial biology, pulmonary innate immunity, and redox biology. After being awarded a VA VISN7 Research Development Award, Dr. Maurice became a staff physician at the Atlanta VA Medical Center and joined the faculty of Emory University School of Medicine. He is at a critical stage in his career development and the support of a CDA-2 will enable him to meet his goal of becoming an independently-funded physician-scientist with a goal of improving the health of the susceptible veteran population at risk for acquiring life-threatening infections.