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

针对肺上皮对肺炎链球菌感染反应中线粒体途径的新疗法

• 批准号: 10367976
• 负责人: Nicholas Michael Maurice
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367976
• 关键词: 8-hydroxyguanosine; Antioxidants; Area; Attenuated; Award; Bacteria; Base Excision Repairs; Bioenergetics; Biogenesis; Biology; Cause of Death; Cell Death; Cells; Chimeric Proteins; Cholesterol; Clinical; Clinical Research; Clinical Trials; Critical Illness; Cytolysins; DNA; DNA Damage; DNA Repair; DNA Repair Enzymes; DNA Repair Pathway; DNA glycosylase; Data; Disease; Elderly; Environment; Enzymes; Epithelial; Epithelial Cells; Event; Faculty; Functional disorder; Funding; Gene Delivery; Generations; Genetic; Goals; Grant; Guanine; Health; Host Defense; Human; Hydrogen Peroxide; Immune; Immune response; Immunization Programs; Impairment; Infection; Inflammatory; Inflammatory Response; Injury; Innate Immune Response; Integration Host Factors; International; Life; Lipids; Lung; Measures; Mediating; Medical center; Mentors; Mentorship; Microbiology; Mitochondria; Mitochondrial DNA; Morbidity - disease rate; Mus; Natural Immunity; Nuclear; Nucleotides; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathogenicity; Pathway interactions; Pharmacology; Physicians; Play; Pneumococcal Infections; Pneumococcal Pneumonia; Pneumonia; Populations at Risk; Process; Proteins; Pseudomonas aeruginosa; Publishing; Pyruvate Oxidase; Quality Control; Reactive Oxygen Species; Research; Research Personnel; Resistance; Respiratory System; Role; Scientist; Sepsis; Severities; Severity of illness; Signal Transduction; Streptococcus pneumoniae; Streptococcus pneumoniae plY protein; Testing; Training; Training Programs; Translations; Universities; Veterans; Virulence; Virulence Factors; Work; attenuation; base; career; career development; cell injury; cell type; community acquired pneumonia; comorbidity; efficacious treatment; epithelial injury; gain of function; immune function; improved; improved outcome; in vivo; in vivo Model; insight; knock-down; lung injury; medical schools; military veteran; mitochondrial dysfunction; mitochondrial genome; mortality; multidisciplinary; mutant; new therapeutic target; novel; novel therapeutic intervention; overexpression; oxidative DNA damage; oxidative damage; pathogenic bacteria; pneumonia model; pre-clinical; repaired; research and development; response; septic patients; skills; success; targeted treatment; tissue injury; translational study; treatment strategy; vaccine development

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.

此CDA-2申请提出了一个为期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致病性的机制，重点是如何相互作用 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调节了 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 包括亚特兰大弗吉尼亚州和埃默里大学的其他高级研究人员， 这些专业知识将有助于莫里斯博士的职业发展。此外，莫里斯博士将受益于 在亚特兰大VA医疗中心和埃默里大学拥有良好的培训环境， 成功发展年轻调查人员职业生涯的记录。莫里斯博士先前发表的研究 确定了细菌病原体铜绿假单胞菌的关键毒力因子， 通过减弱宿主上皮细胞线粒体生物能功能和线粒体 生物起源。他证明了增强线粒体的遗传和药理学策略 生物合成可以促进上皮宿主防御。基于他对线粒体生物发生的研究， 博士莫里斯开始研究另一种线粒体质量控制过程，即线粒体DNA 修复.他也开始关注细菌S。考虑到肺炎对人类健康构成的重大威胁， 老百姓。初步研究已经确定了新的发现，S。肺炎诱导氧化 线粒体DNA损伤并减弱宿主上皮细胞中DNA修复酶OGG 1的表达 细胞额外的数据表明，这一途径可能有显着的后果，上皮宿主 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 例如肺炎球菌溶血素（一种胆固醇依赖性溶细胞素），通过氧化线粒体损害宿主防御 DNA损伤，但线粒体DNA修复的靶向增强可以改善细胞功能障碍， 提高宿主对肺炎球菌感染的反应。这项建议包括三个目标。一是 负责诱导氧化线粒体DNA损伤的肺炎球菌毒力因子， 将鉴定宿主上皮细胞中OGG 1表达的减弱。二、活性氧的作用 上皮宿主中种介导的线粒体损伤和OGG 1介导的线粒体DNA修复 响应S。将定义肺炎。第三，在临床前转化研究中， 靶向线粒体OGG 1的策略将在肺炎球菌肺炎的体内模型中进行测试， 确定增强线粒体DNA修复是否反映了S.肺炎 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， 转化为人类临床研究的潜力。此外，实现这些目标所需的培训将 提供莫里斯博士必要的技能，发展成为一个独立的医生科学家在工作 微生物学、线粒体生物学、肺先天免疫和 氧化还原生物学在被授予VA VISN 7研究发展奖后，莫里斯博士成为了一名员工， 他是亚特兰大退伍军人医疗中心的医生，并加入了埃默里大学医学院。他 正处于职业发展的关键阶段，CDA-2的支持将使他能够实现 成为一个独立资助的物理学家，科学家的目标是改善健康的易感 退伍军人群体面临感染危及生命的疾病的风险。