Inflammation and the Host Responses to Injury

描述（由申请人提供）：该项目旨在提高我们对指导宿主对严重损伤反应的关键调控因素的系统级理解。对严重损伤的先天炎症反应的更深入了解将导致新的基因组和蛋白质组学标记物的发展，这些标记物可以预测结果，并将为进一步的基础和临床研究以及免疫调节干预的目标确定潜在的新途径。该计划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，结合新的宏观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）。6-10年级的具体目标如下：(1)从严重创伤和烧伤住院患者的循环白细胞明确的细胞亚群中确定全基因组表达和细胞蛋白质组。(2)在这些细胞群中，识别与不同临床轨迹和结果相关的先天炎症反应的基因表达模式和蛋白质组反应。(3)利用系统生物学方法，基于从细胞亚群中获得的总细胞蛋白质组学和基因组学，发现新的生物学知识。通过培养和支持包括临床医生、生物化学家、免疫学家、统计学家、计算生物学家和系统生物学家在内的迥然不同学科的研究人员小组，将获得新知识。这些相互作用将导致我们对损伤反应的生物学理解的新范式的发展。项目任务和活动包括：(1)招收580名严重创伤或烧伤患者，采用严格的入院标准和标准化的患者护理指南；(2)富集血白细胞群体的高通量定量、比较蛋白质组学和功能蛋白质组学分析；(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)建立包含临床、生理、蛋白质组学和基因组表达数据的网络创伤相关数据库；(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，最终目标是形成损伤反应的综合系统视图。

DESCRIPTION (provided by applicant): 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.