PLASTICITY OF THE SYSTEMIC INFLAMMATORY RESPONSE

全身炎症反应的可塑性

• 批准号: 8116929
• 负责人: J PERREN COBB
• 金额: $ 5.81万
• 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 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8116929
• 关键词: PLASTICITY; SYSTEMIC; INFLAMMATORY; RESPONSE

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促使人们寻找新型分子诊断方法。该应用的目标是开发一种血液免疫监测策略，可用作新型诊断和预后工具，从而改善对脓毒症风险危重患者的护理。此外，我们寻求对白细胞反应的动态进行建模，并确定功能模块和目标以供进一步研究。我们假设循环白细胞 RNA 的变化可用于模拟宿主炎症反应并改善脓毒症的诊断和预后。我们最近报道，循环白细胞的微阵列分析可用于捕获宿主对呼吸机相关性肺炎（VAP）的反应和恢复的动态。选择 VAP 作为对患者进行研究的败血性损伤，因为它仍然是一种非常常见、病态且昂贵的 ICU 并发症，而且特别难以诊断。我们正在测试白细胞 RNA 信息图（核白细胞图）的临床价值，我们预计这将反映几十年前使用心肌细胞电信息图（心电图）所做的成功努力。我们从工作台转移到床边，使用分子（免疫）制图来测试这种“基因组生命体征”假设。建立了必要的全校范围内的基础设施，以创建涵盖临床、转化研究和计算领域的危重疾病和健康工程中心。这个新的 R01 应用程序的三个相互关联的目标是 1) 根据 85 个基因的循环白细胞 RNA 丰度的变化（核糖图）绘制宿主对 VAP 反应的动态图，2) 确定年龄、性别和种族背景对 VAP 的影响。白细胞转录反应，3) 通过模拟细胞特异性反应来扩展我们对宿主对 VAP 反应的生物学探索。优化的样品采集方案正在使用中。在 3-4 周内从有 VAP 风险的插管儿童和成人中抽取连续血样。数据显示，核白细胞图追踪宿主对 VAP 并发的危重疾病反应的动态，并且这些轨迹因宿主性别、年龄和种族背景的差异而混淆。我们的数据还表明康复患者中存在免疫吸引子状态。公共卫生相关性：外行描述 ICU 中准确诊断感染的持续挑战促使人们寻找新型分子诊断方法。该应用的目标是开发一种血液免疫监测策略，可用作新型诊断和预后工具，从而改善对脓毒症风险危重患者的护理。此外，我们寻求更好地了解白细胞对感染的反应并确定新的治疗靶点。