Inflammation and the Host Responses to Injury

炎症和宿主对损伤的反应

• 批准号: 7939189
• 负责人: RONALD GARY TOMPKINS
• 金额: $ 76.86万
• 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: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7939189
• 关键词: Inflammation; Host; Responses; Injury

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 aproaches (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 epxression 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.

该计划旨在提高我们对指导宿主对严重伤害做出反应的关键监管要素的系统级理解。更好地了解对严重损伤的先天炎症反应将导致开发出可以预测结果的新型基因组和蛋白质组标记，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目标。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，以及新颖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 严重外伤和烧伤后住院的患者。 (2) 在这些细胞群中，识别模式 基因表达和蛋白质组学对与不同疾病相关的先天炎症反应的反应 临床轨迹和结果。 (3)运用系统生物学方法，发现新的生物学知识 基于从细胞亚群获得的总细胞蛋白质组学和基因组学。新的 知识将通过培养和支持截然不同学科的研究小组来获得， 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。 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例的发展。项目任务和活动包括：（1）以严格的入组标准和标准化的患者护理指南招募580名严重创伤或烧伤患者； (2) 对富集的血液白细胞群进行高通量定量、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) 实施一个包含临床、生理、蛋白质组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、重症监护医师和基础医学专家组成的数据解释小组对复杂数据进行计算分析 科学家的最终目标是建立损伤反应的综合系统视图。