Inflammation and the Host Responses to Injury

该计划旨在提高我们对指导东道主应对严重伤害的关键监管要素的系统级别的了解。对严重创伤的先天炎症反应有了更深入的了解，将导致新的基因组和蛋白质组标志物的开发，这些标志物可以预测结果，并将确定进一步基础和临床研究的潜在新途径，以及免疫调节干预的靶点。该计划旨在采用多种高通量分析工具，包括微阵列和比较、定量蛋白质组学，以及新的大尺度和微流体细胞分离方法和生物信息学方法(包括基于知识的途径分析)。第六至第十年的具体目标如下。(1)从严重创伤和烧伤后住院患者循环白细胞的明确细胞亚群中确定全基因组表达和细胞蛋白质组。(2)在这些细胞群体中，确定与不同的临床轨迹和结果相关的先天炎症反应的基因表达和蛋白质组反应模式。(3)利用系统生物学方法，在细胞总蛋白质组学和细胞亚群基因组学的基础上发现新的生物学知识。通过培养和支持截然不同学科的研究人员小组，包括临床医生、生物化学家、免疫学家、统计学家以及计算和系统生物学家，将获得新的知识。这些相互作用将导致我们对伤害反应的生物学理解的新范式的发展。项目的任务和活动包括：(1)以严格的入院标准和标准化的病人护理指南招募580名严重创伤或烧伤患者；(2)对丰富的血液白细胞群体进行高通量的定量、比较蛋白质组和功能蛋白质组分析；(3)使用最先进的高通量格式对这些相同的白细胞群体进行全基因组表达分析；(4)实施与创伤相关的网络数据库，包含临床、生理、蛋白质组和基因组表达数据；(5)由生物统计学家、重症监护医生和基础科学家组成的数据解释小组对复杂数据进行计算分析，最终目标是建立伤害反应的综合系统观点。

The Program seeks to improve our systems-level understanding of the key regulatory elements that direct the host response to serious injury. A greater understanding of the innate inflammatory response to serious injury will lead to the development of novel genomic and proteomic markers that can predict outcome, and will identify potential new avenues for further basic and clinical research, as well as targets for immunomodulatory interventions. The Program is organized to employ multiple high-throughput analytical tools including microarray and comparative, quantitative proteomics coupled with novel macroscale and microfluidics cell separation methodologies and bioinformatics approaches (including knowledge-based pathway analysis). The specific aims in Years 6-10 are as follows. (1) Determine genome-wide expression and the cellular proteome from well-defined cellular subpopulations of circulating leukocytes from hospitalized patients following severe trauma and burn injuries. (2) In these cell populations, identify patterns of gene expression and proteomic responses to the innate inflammatory response associated with different clinical trajectories and outcomes. (3) Using a systems biology approach, discover new biological knowledge based upon total cellular proteomics and genomics obtained from the cellular subpopulations. New knowledge will be obtained by fostering and supporting groups of investigators in vastly disparate disciplines, including clinicians, biochemists, immunologists, statisticians, and computational and systems biologists. These interactions will lead to the development of new paradigms for our biological understanding of the injury response. The project tasks and activities include the following: (1) enrollment of 580 severely traumatized or burned patients with stringent entry criteria and standardized guidelines for patient care; (2) high-throughput quantitative, comparative proteomic and functional proteomic analyses of enriched blood leukocyte populations; (3) genome-wide expression analysis of these same leukocyte populations using state-of-the-art high throughput formats; (4) implementation of a web-enabled trauma-related database containing clinical, physiologic, proteomic, and genomic expression data; (5) computational analysis of the complex data by data interpretation groups, comprised of biostatisticians, critical care physicians and basic scientists with the ultimate goal being an integrated systems view of the injury response.