PLASTICITY OF THE SYSTEMIC INFLAMMATORY RESPONSE

全身炎症反应的可塑性

• 批准号: 8137981
• 负责人: J PERREN COBB
• 金额: $ 34.7万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8137981
• 关键词: Abdomen; Adult; Age; Biological Assay; Biology; Blood; Blood specimen; Caring; Cell model; Child; Childhood; Clinical; Complication; Critical Illness; Data; Data Analyses; Diagnosis; Diagnostic; Electrocardiogram; Engineering; Enrollment; Funding; Gender; Gene Expression; Genes; Genomics; Goals; Graph; Health; Human Volunteers; Immune; Immune response; Immunologic Monitoring; Infection; Inflammation; Inflammatory Response; Intravenous; Laboratories; Leukocytes; Maps; Microarray Analysis; Modeling; Molecular; Mus; Muscle Cells; Operative Surgical Procedures; Patients; Plasma; Pneumonia; Proteome; Protocols documentation; RNA; Recovery; Reporting; Research Infrastructure; Research Project Grants; Respiratory Diaphragm; Risk; Sepsis; Side; Signal Transduction; System; Testing; Time Series Analysis; Translational Research; Trauma; United States National Institutes of Health; Universities; Ventilator; age effect; base; bench to bedside; cell injury; cohort; computerized tools; cytokine; improved; monocyte; mouse model; new technology; new therapeutic target; novel; novel diagnostics; procalcitonin; prognostic; programs; response; sample collection; septic; tool; volunteer

DESCRIPTION (provided by applicant): The ongoing challenge of accurately diagnosing infection in the ICU motivates a search for novel molecular diagnostics. The goal of this application is to develop a strategy for blood immunomonitoring that can be used as a novel diagnostic and prognostic tool, thereby improving the care of critically ill patients at risk for sepsis. In addition, we seek to model the dynamics of the leukocyte response and identify functional modules and targets for further study. We hypothesize that changes in circulating leukocyte RNA can be used to model the host inflammatory response and improve sepsis diagnostics and prognostics. We reported recently that microarray analysis of circulating leukocytes can be used to captures the dynamics of the host response to and recovery from ventilator- associated pneumonia (VAP). VAP was chosen as the septic insult to study in patients, as it remains a very common, morbid, and expensive ICU complication that is particularly difficult to diagnose. We are testing the clinical value of a graph of RNA information from leukocytes (the riboleukogram), which we expect will mirror the successful efforts made decades ago using a graph of electrical information from myocytes (electrocardiogram). We moved from the bench to the bedside to test this "genomic vital sign" hypothesis using molecular (immune) cartography. The requisite University-wide infrastructure was established to create the Center for Critical Illness and Health Engineering, which spans clinical, translational research, and computational domains. The three interlocking aims of this new R01 application are 1) Map the dynamics of the host response to VAP based upon changes in circulating leukocyte RNA abundance for 85 genes (riboleukograms), 2) Determine the effect of age, gender, and ethnic background on the leukocyte transcriptional response, and 3) Expand our exploration of the biology of the host response to VAP by modeling cell-specific responses. The optimized sample collection protocols are in use. Serial blood samples are drawn over 3-4 weeks from intubated children and adults at risk for VAP. Data are presented demonstrating that riboleukograms track the dynamics of the host response to critical illness complicated by VAP, and that these trajectories are confounded by differences in host gender, age, and ethnic background. Our data also indicate the existence of an immunological attractor state in recovering patients. PUBLIC HEALTH RELEVANCE: Lay Description The ongoing challenge of accurately diagnosing infection in the ICU motivates a search for novel molecular diagnostics. The goal of this application is to develop a strategy for blood immune monitoring that can be used as a novel diagnostic and prognostic tool, thereby improving the care of critically ill patients at risk for sepsis. In addition, we seek to better understand the response of white blood cells to infection and to identify new therapeutic targets.

描述（由申请人提供）：在ICU中准确诊断感染的持续挑战激发了寻找新型分子诊断的搜索。该应用的目的是制定一种可以用作新型诊断和预后工具的血液免疫监测策略，从而改善对患有脓毒症风险的重症患者的护理。此外，我们试图对白细胞反应的动力学进行建模，并确定功能模块和目标以进行进一步研究。我们假设循环白细胞RNA的变化可用于对宿主炎症反应进行建模并改善败血症诊断和预后。我们最近报道说，循环白细胞的微阵列分析可用于捕获宿主反应的动力学和从呼吸机相关的肺炎（VAP）中恢复的动力学。 VAP被选为对患者进行研究的化粪池侮辱，因为它仍然是一种非常普遍，病态且昂贵的ICU并发症，尤其难以诊断。我们正在测试白细胞（Riboleukogram）RNA信息图的临床值，我们期望这将反映几十年前使用来自心肌细胞（心电图）的电气信息图所做的成功努力。我们从长凳上移到床边，使用分子（免疫）制图测试了这种“基因组生命体征”假设。建立了必要的大学范围内基础设施，以创建跨越临床，转化研究和计算领域的重症疾病和卫生工程中心。该新的R01应用的三个互锁目的是1）根据85个基因的循环白细胞RNA丰度的变化（核糖表现图），2）确定年龄，性别和种族背景对白细胞转录响应的影响，并根据我们的生物探索的生物学响应，确定了年龄，性别和种族背景对vap eSt vap的生物响应的范围，请绘制主机对VAP的动态。正在使用优化的样本收集协议。从插管儿童和成人有烟气风险的插管儿童和成人3-4周，串行血液样本。显示了数据表明，核糖底图跟踪了VAP复杂的宿主对危害疾病的反应的动力学，并且这些轨迹被宿主性别，年龄和种族背景的差异所困扰。我们的数据还表明，在恢复患者中存在免疫吸引力状态。公共卫生相关性：介绍在ICU中准确诊断感染的持续挑战激励寻找新型分子诊断。该应用的目的是制定一种可以用作新型诊断和预后工具的血液免疫监测策略，从而改善了患有败血症风险的重症患者的护理。此外，我们试图更好地理解白细胞对感染和鉴定新的治疗靶标的反应。