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

基本信息

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
项目类别：
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

项目摘要

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.

该CDA-2申请提案为期5年的培训计划，以发展Nicholas Maurice博士的职业为他研究了肺炎链球菌致病性的机制，重点是相互作用自由基病毒因子和宿主线粒体氧化物DNA损伤和修复调节对肺炎球菌感染的先天免疫反应。他的主要导师Ruxana Sadikot博士是国际公认的宿主防御细菌病原体领域的专家。他的攻击团队包括弗吉尼亚州亚特兰大和埃默里大学的其他高级调查员将有助于莫里斯博士的职业发展的专业知识。此外，莫里斯博士将从亚特兰大弗吉尼亚州医学中心和埃默里大学的良好培训环境具有良好的轨道成功发展年轻调查员职业的记录。莫里斯博士先前发表的研究鉴定出细菌病原体的关键病毒因子铜绿假单胞菌，损害了先天性通过衰减宿主上皮细胞线粒体生物能功能和线粒体的免疫力生物发生。他证明了增强线粒体的遗传和药物策略生物发生可以促进上皮宿主防御。根据他研究线粒体生物发生的工作， Maurice博士开始研究另一个线粒体质量控制过程，即线粒体DNA 维修。他还开始专注于细菌S.肺炎，给予了巨大的健康威胁。资深人口。初步研究已经确定了肺炎链球菌诱导氧化的新发现。线粒体DNA损伤并减弱宿主上皮中DNA修复酶的表达细胞。其他数据表明，该途径可能会对上皮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因子因子的假设例如肺炎，胆固醇依赖性细胞溶素，通过氧化线粒体损害宿主防御 DNA损伤，但有针对性的线粒体DNA修复可以改善细胞功能障碍，并且改善宿主对肺炎球菌感染的反应。该提案包括三个目标。首先，负责诱导氧化线粒体DNA损伤的肺炎球菌病毒因素和将确定宿主上皮细胞中OGG1表达的衰减。其次，活性氧的作用物种介导的线粒体损伤和上皮宿主中的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，新疗法靶向线粒体OGG1的策略将在肺炎球菌肺炎的体内模型中进行测试确定增强线粒体DNA修复是否反映了肺炎链球菌的有效治疗策略感染。这些研究将提供有关具有具有的宿主链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向莫里斯博士提供发展为开发成独立的物理科学家所需的技能微生物学，线粒体生物学，肺部先天免疫和氧化还原生物学。在获得VA VISN7研究开发奖后，Maurice博士成为了员工亚特兰大弗吉尼亚州医疗中心的医师，并加入了埃默里大学医学院的学院。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自己的目标成为一名独立资助的身体科学家，目的是改善易感性的健康退伍军人有可能获得威胁生命的感染的风险。