Immune profiling to stratify Clostridioides difficile infection outcomes

通过免疫分析对艰难梭菌感染结果进行分层

• 批准号: 10282875
• 负责人: Gregory Russell Madden
• 金额: $ 19.22万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-12 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10282875
• 关键词: Antibiotic Resistance; Antibodies; Arizona; Award; Biological Markers; Biometry; Blood; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinical; Clinical Data; Clinical Markers; Clinical Research; Clinical Trials Design; Clostridium difficile; Colectomy; Colorectal Surgery; Communicable Diseases; Data; Data Science; Databases; Development Plans; Diagnosis; Diagnostic; Disease; Doctor of Philosophy; Enteral; Environment; Epidemiologist; Epidemiology; Feces; Funding; Goals; Health Sciences; Healthcare; Hospital Mortality; Hospitals; Host Defense; IL8 gene; Immune; Immune system; Immunity; Immunologic Markers; Immunologics; Immunology; Infection; Innate Immune System; Institutes; Institution; Interleukin-15; Interleukin-6; K-Series Research Career Programs; Lead; Life; Literature; Machine Learning; Master' s Degree; Measures; Mediating; Medical; Mentors; Metadata; Methods; Michigan; Modeling; Molecular; National Institute of Allergy and Infectious Disease; Operative Surgical Procedures; Organism; Outcome; Pathogenesis; Pathogenicity; Patients; Performance; Play; Predictive Analytics; Public Health Schools; RANTES; Research; Research Personnel; Resources; Risk; Risk Assessment; Risk Factors; Role; Schools; Science; Sepsis; Serum; Standardization; Statistical Models; System; TNF gene; Techniques; Testing; Therapeutic; Time; Toxin; Training Activity; Universities; Virginia; Work; adverse outcome; antitoxin; base; biobank; career development; cytokine; eosinophil; experience; fecal transplantation; healthcare-associated infections; innovation; microbiome; molecular diagnostics; mortality; novel; novel marker; novel therapeutics; outcome prediction; pathogen; precision medicine; predictive modeling; professor; prospective; receptor; response; risk stratification; specific biomarkers; stool sample; translational scientist

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.

候选人：Gregory Madden 博士是弗吉尼亚大学传染病学助理教授 在艰难梭菌感染的诊断、流行病学和发病机制方面的研究经验。 职业发展计划和目标：拟议的 K23 指导职业发展奖将独特地 将 Madden 博士培养为转化研究员，拥有宿主与病原体相互作用方面的经验和先进的技术 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 和统计建模，最终获得临床研究理学硕士学位。 研究计划：艰难梭菌是美国主要的医疗保健相关病原体。证据 表明宿主先天免疫系统（特别是 2 型或嗜酸性粒细胞介导的免疫）、粪便 C. 艰难梭菌负荷和二元毒素在艰难梭菌感染中发挥重要作用。但是没有模型可以预测 艰难梭菌感染的结果考虑了这些因素。我们实验室的数据显示，嗜酸性粒细胞减少症， 病原免疫的特异性生物标志物（即可溶性 ST2 受体，IL-6）、粪便微生物负荷以及 粪便二元毒素的存在与艰难梭菌死亡率增加有关。 Madden 博士建议：1) 构建艰难梭菌患者的临床免疫学数据库，以开发基于生物标志物的稳健药物 艰难梭菌感染结果模型，2) 与领先的模型一起前瞻性验证该模型 临床模型。成功完成拟议的研究将为艰难梭菌创建一个经过验证的免疫特征。 艰难梭菌感染的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急需最佳方法来对危及生命的艰难梭菌感染进行分层 诊断时间。 导师：Madden 博士的导师是 William A. Petri 博士，医学博士、哲学博士，宿主防御领域的领先研究员 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（Costi 博士） Sifri，一位出色的执业医院流行病学家，具有研究分子发病机制的背景）， 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，医学博士）和分子诊断（Eric R. Houpt，医学博士）。 环境：弗吉尼亚大学因其在肠道疾病方面的工作而闻名于世，并且是最早的大学之一 机构建立一所致力于数据科学的学院。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 Petri 实验室将提供资源 以及该候选人作为独立调查员蓬勃发展的多元化和激励性的环境 在这个前沿领域。