Immune profiling to stratify Clostridioides difficile infection outcomes

候选人：格雷戈里·马登博士是弗吉尼亚大学传染病学助理教授， 艰难梭菌感染的诊断、流行病学和发病机制研究经验。 职业发展计划和目标：拟议的K23导师职业发展奖将是独一无二的 使马登博士成为一名翻译研究员，具有宿主-病原体相互作用方面的经验和高级 建模技术。该奖项的培训活动包括临床试验设计的研究生课程 以及统计建模，最终获得临床研究理学硕士学位。 研究计划：艰难梭状芽孢杆菌是美国主要的医疗保健相关病原体。证据 提示宿主的先天免疫系统(尤其是2型或嗜酸性粒细胞介导的免疫)、粪便中的C. 艰难梭菌的负担和二元毒素在艰难梭菌感染中起重要作用。然而，没有可预测的模型 艰难梭菌感染的结果考虑到了这些因素。我们实验室的数据显示，嗜酸性粒细胞减少症， 致病免疫的特定生物标志物(即可溶性ST2受体，IL-6)，粪便生物负荷，以及 粪便二元毒素的存在与艰难梭菌死亡率的增加有关。马登博士建议：1) 构建艰难梭菌患者的临床免疫学数据库以开发强有力的生物标志物 艰难梭菌感染结局的模型和2)与领先的 临床模型。这项拟议研究的成功完成将为C. 艰难梭菌感染结果反映了我们对发病机制的最新理解。此外，我们将确定一个 研究人员和临床医生亟需的最佳方法来对危及生命的艰难梭菌感染进行分层 诊断的时间。 导师：马登博士的导师是威廉·A·佩里博士，医学博士，博士，宿主防御领域的领先研究人员 对抗艰难梭菌。内部顾问和合作者在医院流行病学方面拥有不同的专业知识(科斯蒂博士 Sifri，具有分子发病机制研究背景的执业医院流行病学家)， 免疫学(Melanie Rutkowsi博士，博士，生物统计学/机器学习(Jennie Ma，博士)，临床试验设计 (James A.Platts-Mills博士，医学)和分子诊断学(Eric R.Houpt，医学博士)。 环境：弗吉尼亚大学以其在肠道疾病方面的研究而闻名于世，也是首批 各机构将建立一所致力于数据科学的学校。弗吉尼亚大学数据科学研究所， 公共卫生科学学院、医院流行病学办公室和皮涅拉实验室将提供资源 以及这位候选人作为一名独立调查员蓬勃发展的多样化和激动人心的环境 在这个尖端领域。

Candidate: Dr. Gregory Madden is an Assistant Professor of Infectious Diseases at the University of Virginia with experience in research regarding the diagnosis, epidemiology, and pathogenesis of C. difficile infection. Career Development Plan and Goals: The proposed K23 Mentored Career Development Award will uniquely establish Dr. Madden as a translational researcher with experience in host-pathogen interactions and advanced modeling techniques. Training activities for the award include graduate-level coursework in clinical trial design and statistical modeling, culminating with a Master’s Degree of Science in Clinical Research. Research Plan: Clostridioides difficile is the leading healthcare-associated pathogen in the US. Evidence suggests that the host innate immune system (particularly Type 2, or eosinophil-mediated immunity), fecal C. difficile burden, and Binary toxin play important roles in C. difficile infection. However, no model to predict outcomes of C. difficile infection takes these factors into account. Data from our lab show that eosinopenia, specific biomarkers of pathogenic immunity (i.e., Soluble ST2 Receptor, IL-6), fecal organism burden, and the presence of fecal Binary Toxin are associated with increased C. difficile mortality. Dr. Madden, proposes to: 1) Construct a clinical-immunologic database of C. difficile patients to develop a robust biomarker-based model for outcomes of C. difficile infection and 2) Prospectively validate this model alongside the leading clinical models. Successful completion of the proposed research will create a validated immune profile for C. difficile infection outcomes that reflects our latest understanding of pathogenesis. In addition, we will identify a much-needed optimal approach for researchers and clinicians to stratify life-threatening C. difficile infection at the time of diagnosis. Mentors: Dr. Madden’s mentor is Dr. William A. Petri, MD, PhD, a leading researcher in the field of host defense against C. difficile. Internal advisors and collaborators have diverse expertise in hospital epidemiology (Dr. Costi Sifri, accomplished practicing hospital epidemiologist with a background studying molecular pathogenesis), immunology (Dr. Melanie Rutkowsi, PhD, biostatistics/machine learning (Jennie Ma, PhD), clinical trial design (Dr. James A. Platts-Mills, MD), and molecular diagnostics (Eric R. Houpt, MD). Environment: The University of Virginia is world-renowned for its work in enteric diseases and is one of the first institutions to establish a School dedicated to Data Science. The University of Virginia Data Science Institute, School of Public Health Sciences, Office of Hospital Epidemiology, and the Petri Lab will provide the resources as well as the diverse and stimulating environment for this Candidate to flourish as an independent investigator in this cutting-edge field.