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：
10550131
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/10550131
关键词：
8-Oxoguanine DNA Glycosylase 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 Communicable Diseases Critical Illness Cytolysins DNA DNA Damage DNA Repair DNA Repair Enzymes DNA glycosylase Data Disease Elderly Environment Enzymes Epithelial Cells Epithelium 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 Oxidative Stress Induction Pathogenesis Pathogenicity Pathway interactions Physicians Pneumococcal Infections Pneumococcal Pneumonia Pneumonia Populations at Risk Predisposition 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 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 migration military veteran mitochondrial dysfunction mitochondrial genome mortality multidisciplinary mutant new therapeutic target novel novel therapeutic intervention overexpression oxidative DNA damage oxidative damage pathogenic bacteria pharmacologic pneumonia model pre-clinical repaired research and development response septic patients skills success targeted treatment tissue injury translational potential 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.

此 CDA-2 申请提出了为期 5 年的培训计划，以将 Nicholas Maurice 博士的职业发展为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氧化DNA损伤和修复之间的调节他的主要导师 Ruxana Sadikot 博士是一位对肺炎球菌感染的先天免疫反应。他的指导团队是宿主防御细菌病原体领域的国际公认专家。包括亚特兰大退伍军人管理局和埃默里大学的其他高级研究人员，其互补领域包括有助于莫里斯博士职业发展的专业知识此外，莫里斯博士还将受益于亚特兰大退伍军人医疗中心和埃默里大学拥有良好的培训环境和经过验证的赛道莫里斯博士之前发表的研究成果。确定了细菌病原体铜绿假单胞菌的关键毒力因子，该因子会损害先天性通过减弱宿主上皮细胞线粒体生物能功能和线粒体的免疫他证明了增强线粒体的遗传和药理学策略。根据他对线粒体生物发生的研究，生物发生可以促进上皮宿主防御。 Maurice 博士开始研究另一种线粒体质量控制过程，即线粒体 DNA 鉴于肺炎链球菌对健康构成重大威胁，他还开始关注它。初步研究发现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细胞中 DNA 修复酶 OGG1 的表达其他数据表明该途径可能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提出了肺炎球菌毒力因子的假设。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，但有针对性地增强线粒体 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。该提案包括三个目标。肺炎球菌毒力因子负责诱导氧化线粒体 DNA 损伤和宿主上皮细胞中OGG1表达的减弱将被确定其次，活性氧的作用。上皮宿主中物种介导的线粒体损伤和 OGG1 介导的线粒体 DNA 修复第三，在临床前转化研究中，将确定新的治疗方法。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这些研究将为宿主与肺炎球菌的相互作用提供新的见解。此外，实现这些目标所需的培训将具有转化为人类临床研究的潜力。为莫里斯博士提供发展成为在该机构工作的独立医师科学家所需的技能微生物学、线粒体生物学、肺先天免疫等多学科领域的交叉点莫里斯博士获得 VA VISN7 研究开发奖后，成为一名工作人员。亚特兰大退伍军人管理局医学中心的医生，并加入埃默里大学医学院。正处于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医师科学家，目标是改善脆弱性的健康状况退伍军人群体面临感染危及生命的感染的风险。