Predicting and Preventing Acute Respiratory Distress Syndrome after Hematopoietic Stem Cell Transplantation

项目总结/摘要 造血干细胞移植（HSCT）为以下疾病提供了先进的治疗选择： 否则无法治愈肺部并发症在HSCT后很常见，并严重损害其 整体成功率。最严重的是急性呼吸窘迫综合征（ARDS）， HSCT后发生率为5%，死亡率> 60%。有效的治疗方法是 如果没有，开发新的方法来预防ARDS可能会更成功地改善患者的预后。 两个关键的知识差距使制定成功的预防战略变得困难：1）无法 在ARDS发生之前可靠地识别高危患者; 2）对ARDS的不完全理解 HSCT后ARDS的机制和亚型。本申请的科学目标是解决 这些关键的知识差距，通过以下具体目标： 1)开发并验证风险预测模型，包括移植前、移植后和移植中 医院的危险因素，可以帮助确定哪些患者最有可能发展HSCT后ARDS。 2)Prostaglandin评估HSCT后ARDS高危患者的代谢组学并利用 临床、生物标志物和代谢组学数据，以探索HSCT后ARDS的内表型。 目标1利用高度创新的数据提取技术来开发实时连续的ARDS风险 对接受HSCT患者的监测系统。目的2评估代谢组学的作用， 分析工具，在推进机制的理解，为什么病人发展后HSCT ARDS，以及 最近描述的ARDS内源性表型是否可以被鉴定为HSCT后的ARDS。 申请人的长期目标是：1）成为一名独立的翻译临床医生-科学家， 一个多学科研究小组专注于改善呼吸道疾病患者的预后 HSCT后并发症，2）制定有效的策略来预防HSCT后ARDS，这是最重要的 严重的移植后并发症申请人的培训目标是发展先进的 统计学、生物医学建模、机器学习和代谢组学方面的技能，以促进这些长期目标的实现。 为了满足这些培训需求，申请人制定了全面的职业发展计划， 包括上述培训需求领域的有针对性的教学机会，并提供额外的“实践”机会 在所有这些领域的经验。导师团队和研究环境非常适合 申请人的需求，结合重症监护信息学和代谢组学的专业知识， 学术移植中心该提案通过努力改善患者的结局来支持NIH的使命 移植后发生呼吸衰竭的患者，同时培训初级研究员的基本技能， 这是他向独立研究过渡的必要条件。

PROJECT SUMMARY/ABSTRACT Hematopoietic stem cell transplantation (HSCT) offers an advanced treatment option for conditions that are otherwise incurable. Pulmonary complications are common following HSCT and severely compromise its overall success rate. The most severe end of this spectrum is acute respiratory distress syndrome (ARDS), which occurs in 5% of patients following HSCT, with a mortality >60%. As effective treatments for ARDS are lacking, developing new ways to prevent ARDS is likely to be more successful in improving patient outcomes. Two critical knowledge gaps make developing successful prevention strategies difficult: 1) an inability to reliably identify high-risk patients before ARDS has developed and; 2) an incomplete understanding of the mechanisms and subtypes of post-HSCT ARDS. The scientific objectives of this application are to address these critical knowledge gaps through the following Specific Aims: 1) Develop and validate a risk-prediction model incorporating pre-transplant, post-transplant and in- hospital risk factors that can help identify which patients are most likely to develop post-HSCT ARDS. 2) Prospectively evaluate metabolomics in patients at high-risk of developing post-HSCT ARDS and utilize clinical, biomarker and metabolomics data to explore endophenotypes of post-HSCT ARDS. Aim 1 leverages highly innovative data extraction techniques to develop a real-time continuous ARDS risk surveillance system for patients who undergo HSCT. Aim 2 evaluates the role of metabolomics, an emerging analytic tool, in advancing mechanistic understanding of why patients develop post-HSCT ARDS, as well as whether recently described ARDS endophenotypes can be identified post-HSCT ARDS. The applicant’s long-term goals are to: 1) become an independent translational clinician-scientist leading a multidisciplinary research team focused on improving outcomes of patients who develop respiratory complications after HSCT, and 2) develop effective strategies to prevent post-HSCT ARDS, one of the most significant post-transplant complications today. The training goals of the applicant are to develop advanced skills in statistics, biomedical modeling, machine learning, and metabolomics to facilitate these long-term goals. To address these training needs, the applicant has constructed a comprehensive career development plan that includes targeted didactic opportunities in the areas of training need above, with additional “hands-on” experience in all of these areas. The mentorship team and research environment is uniquely well suited to the applicant’s needs, combining expertise in critical care informatics and metabolomics at a high-volume academic transplant center. The proposal supports the NIH mission by striving to improve outcomes of patients who develop respiratory failure after transplantation, while training a junior investigator in the essential skills necessary for his transition to research independence.