Viral and Host Biomarkers of Human Rhinovirus Disease Severity in Transplantation

 描述（由申请人提供）：本提案描述了一个为期五年的研究培训计划，该计划将使我能够实现成为一名独立的临床学术研究人员的目标，重点关注免疫功能低下宿主的呼吸道病毒感染。我的目标是通过更好地定义人类鼻病毒（HRV）和其他呼吸道病毒感染不良结局的风险，并应用这些知识开发疾病严重程度的生物标志物，来改善患者移植相关传染病的结局。该建议基于我在临床传染病，流行病学和生物统计方法以及实验室科学方面的培训，并提供了一个详细的计划，以提高我对病毒学，免疫学和遗传学的知识，进行前瞻性队列研究和基因表达统计分析。该提案结合了一组优秀导师的专业知识，包括传染病，流行病学，统计学和数据建模方面的专家，他们致力于确保该项目的成功以及我作为独立临床研究人员的职业发展。 该提案的第一个目的涉及分析决定HRV感染疾病严重程度的病毒因素。具体而言，我将确定血清和呼吸道样本中病毒载量、病毒种属类型和病毒脱落对疾病结局（包括下呼吸道疾病进展和死亡率）的作用。该提案的成功得到了对来自大型患者队列的回顾性和前瞻性收集的标本进行统一分子检测的独特机会的支持，从而有机会开发多变量模型并调整多个临床协变量。对于我的第二个目标，我将通过分析决定疾病严重程度的细胞因子谱和基因表达谱来确定宿主因素。再次利用对大量HCT接受者的访问和建立的前瞻性样本收集方案，我将能够开发出强大的生物标志物，这些生物标志物将为免疫功能低下的宿主在HRV感染期间的生物学途径提供重要的见解。 通过完成本提案中的目标，我将大大有助于我们对移植中HRV感染影响的了解，以及我们使用病毒和宿主生物标志物预测疾病严重程度的能力。尽管移植实践有所改善，但HRV仍然是HCT受者感染性死亡的重要原因。生物标志物的鉴定具有指导早期和特异性诊断工具的潜力，并将为制定预防和治疗策略提供基础。最终，该提案将使我能够开发一个更大的研究计划，以提高我们对免疫功能低下宿主呼吸道病毒感染的理解和影响结果，然后可以应用于其他脆弱人群，包括婴儿，老年人和先前存在心脏或肺部疾病的个人。

 DESCRIPTION (provided by applicant): This proposal describes a five-year research training program that will allow me to achieve my goal of becoming an independent clinically-oriented academic researcher, focusing on respiratory viral infections in immunocompromised hosts. My goal is to improve patient transplant-related infectious disease outcomes through better defining risks for poor outcomes in human rhinovirus (HRV) and other respiratory viral infections, and applying this knowledge to develop biomarkers for disease severity. This proposal builds upon my training in clinical infectious diseases, epidemiologic and biostatistical methods and laboratory-based science, and provides a detailed plan to improve my knowledge of virology, immunology and genetics, conducting prospective cohort studies, and gene expression statistical analysis. This proposal incorporates the expertise of an outstanding group of mentors, including experts in infectious diseases, epidemiology, statistics, and data modeling, who are dedicated to ensuring the success of this project and the development of my career as an independent clinical researcher. The first aim of this proposal involves the analysis of viral factors that determine disease severity in HRV infection. Specifically, I will determine the role o viral load in serum and respiratory samples, viral species type, and viral shedding on disease outcomes including progression to lower tract disease and mortality. The success of this proposal is bolstered by the unique opportunity to perform uniform molecular testing on both retrospectively and prospectively collected specimens from a large cohort of patients, allowing the opportunity to develop multivariable models and adjust for multiple clinical covariates. For my second aim, I will identify host factors through the analysis of cytokine profiles and gene expression profiles that determine disease severity. Again utilizing access to a large cohort of HCT recipients and established prospective sample collection protocols, I will be able to develop robust biomarkers that will provide important insight into biologic pathways during HRV infection in immunocompromised hosts. Through accomplishing the aims in this proposal, I will contribute significantly to our knowledge of the impact of HRV infection in transplantation, and our ability to use viral and host biomarkers to predict disease severity. Despite improvements in transplant practices, HRV remains a significant cause of infectious mortality in HCT recipients. Identification of biomarkers has the potential to guide early and specific diagnostic tools and wil provide a basis to develop prevention and treatment strategies. Ultimately, the proposal will allow me to develop a larger research program to improve our understanding and affect outcomes of respiratory viral infections in immunocompromised hosts, which can then be applied to other vulnerable populations including infants, the elderly, and individuals with preexisting heart or pulmonary conditions.