Bedside Genomics in Severe Trauma

描述（由申请人提供）：严重创伤不仅仍然是住院和发病的主要原因，而且也是45岁以下个人死亡的主要原因。创伤后感染、败血症和MSOF的发生频率仍然很高，这在很大程度上是由于宿主对严重创伤的免疫反应的异质性，以及入院后早期无法准确识别有免疫异常的患者，因此这些患者面临复杂结局的高风险。我们的首要假设是，严重钝性创伤后人类血液白细胞转录组的早期变化（<12-24小时）可用于识别将有不良临床结果的患者，以及最终可能从针对先天性和适应性免疫反应的干预治疗中受益的患者。我们建议开发一个临床床边平台，基于总和富集的血液白细胞群的基因组表达模式，在此基础上开发基于基因组学的重症患者床边快速诊断，并可整合到临床治疗方案中。有三个具体目标：(1)利用来自400多名创伤患者的现有RNA样本和来自“炎症”胶水资助的2300多名创伤患者的数据库，开发基于白细胞转录组的统计模型，该模型可用于预测严重创伤后复杂的临床结果；(2)开发一种护理点设备，可以在床边分离血液白细胞和pmn，并在几小时内使用NanoString技术测定mRNA丰度；(3)对75例严重创伤患者的统计模型和护理点装置进行前瞻性验证，以识别具有复杂临床轨迹风险的患者。该项目的成功完成将创造一种基于基因组学的诊断方法，可以在临床环境中提供及时的基因组数据，预测危重创伤患者的临床结果。这一努力的成功将大大有助于实现整合生物技术、基因组学和生物信息学的目标，改变临床实践，并为危重患者提供个性化医疗的概念。

DESCRIPTION (provided by applicant): Severe trauma not only remains a major cause of hospitalization and morbidity, but is also the leading cause of death in individuals under the age of 45. The frequency of post-trauma infections, sepsis, and MSOF remain all too frequent due, in large part, to the heterogeneity of the host immune response to severe trauma, and the inability to accurately identify patients who have immunological abnormalities early after admission and who are therefore at high risk of complicated outcomes. Our overarching hypothesis is that early changes in the human blood leukocyte transcriptome (<12-24 hrs) after severe blunt trauma can be used to identify patients who will have an adverse clinical outcome, and who ultimately may benefit from intervention therapies targeting innate and adaptive immune responses. We propose to develop a clinical bed-side platform, based on genomic expression patterns from total and enriched blood leukocyte populations, on which to develop a rapid genomics-based diagnostic at the bedside in severely injured patients, which can be integrated into clinical treatment programs. There are three specific aims: (1) Using existing RNA samples from over 400 trauma patients and a database of over 2,300 trauma patients from the "Inflammation" Glue Grant, develop statistical models based on the leukocyte transcriptome that can be validated for predicting a complicated clinical outcome after severe trauma; (2) develop a point of care device that can isolate blood leukocytes and PMNs at the bedside and determine mRNA abundance in a matter of hours using a NanoString" technology; and (3) validate prospectively in 75 severe trauma patients the statistical model and point of care device to identify patients at risk of having a complicated clinical trajectory. Successful completion of the program will create a genomics-based diagnostic that can provide in the clinical setting, timely genomic data predictive of clinical outcomes in critically ill trauma patients. Success in this endeavor will go far to reach the goals to integrate biotechnology, genomics and bioinformatics, to change clinical practice, and to invigorate the concept of personalized medicine in the critically ill patient.