Bioinformatics Analysis of Control Mechanisms of Hypermetabolism

代谢亢进控制机制的生物信息学分析

• 批准号: 7917172
• 负责人: IOANNIS P ANDROULAKIS
• 金额: $ 30.32万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7917172
• 关键词: Accidental Injury; Acute; Acute-Phase Reaction; Address; Affect; Amino Acids; Animal Model; Animals; Bioinformatics; Biomedical Engineering; Burn Trauma; Burn injury; Caring; Catabolism; Cause of Death; Critical Illness; DNA Microarray Chip; Data; Effectiveness; Engineering; Fire - disasters; Gene Expression; Goals; Hospitalization; Immune response; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Insulin; Intervention; Lead; Ligation; Liver; Maintenance; Medical; Metabolic; Metabolism; Methods; Microarray Analysis; Modeling; Molecular; Molecular Profiling; Monitor; Morbidity - disease rate; Nitrogen; Nutritional Support; Outcome; Patients; Phase; Proteins; Rattus; Recovery; Regulation; Reporting; Resolution; Sepsis; Signal Transduction; Skeletal Muscle; Supplementation; Testing; Therapeutic; Time; United States; combat; cytokine; heat injury; improved; in vivo; inhibitor/antagonist; mortality; novel; public health relevance; response; secondary infection; septic; small molecule; transcription factor

DESCRIPTION (provided by applicant): Fires and burns are among the most common causes of death from unintentional injury. In the United States, almost 1.2 million burn injuries are reported annually and despite significant advances in burn care, infection remains a major cause of morbidity and mortality in burn patients. A better understanding of a patient's response to the burn injury and the implications of secondarily acquired infections will have a profound impact on hospitalization, medical care, treatment and, survival of burn patients. Major thermal injury is associated with hypermetabolism and catabolism. For reasons that are not yet clearly understood, severe burns and trauma can lead to an uncontrolled and prolonged action of pro-inflammatory cytokines. The extent of the inflammatory response has been shown to inversely correlate with survival. Studies suggest that blunting the excessive inflammatory signal cascade may be an efficient strategy to improve patient outcomes after burn injury. Our proposal aims at addressing two questions: (i) what are the cellular and molecular signatures of prolonged inflammation; and (ii) what targets modulate the in vivo response. Specific Aim 1 will test the hypothesis that prolonged inflammation induces significant pathophysiological responses which can be characterized by monitoring dynamic changes in gene expression and metabolic fluxes. Specific Aim 2 will test the hypothesis that advanced bioinformatics methods can identify critical points of control of the inflammatory response. Specific Aim 3 will test the hypothesis that the hypermetabolic response can be modulated by interfering with the critical points of control identified in Aim 2. These studies represent a comprehensive approach integrating data at the gene expression, and metabolic flux levels obtained during the onset and maintenance of hypermetabolism. An investigative team has been assembled which brings together key expertise in burn animal models and hypermetabolism (Berthiaume), molecular bioengineering (Roth), metabolic engineering (Ierapetritou) and bioinformatics (Androulakis) PUBLIC HEALTH RELEVANCE: This proposal aims towards the understanding of the control mechanisms of the hypermetabolic response of burn-sepsis induced inflammation using data collected from an animal (rat) model. Our ultimate goal is to understand the systemic response in our efforts to, eventually, suggest improve therapeutic strategies for the recovery from severe burn injuries.

描述（由申请人提供）：火灾和烧伤是意外伤害导致死亡的最常见原因之一。在美国，每年报告近 120 万例烧伤，尽管烧伤护理取得了重大进展，但感染仍然是烧伤患者发病和死亡的主要原因。更好地了解患者对烧伤的反应以及继发性感染的影响将对烧伤患者的住院、医疗护理、治疗和生存产生深远的影响。主要的热损伤与代谢亢进和分解代谢有关。由于尚不清楚的原因，严重烧伤和创伤可能导致促炎细胞因子的失控和长期作用。炎症反应的程度已被证明与生存呈负相关。研究表明，减弱过度的炎症信号级联可能是改善烧伤后患者预后的有效策略。我们的建议旨在解决两个问题：（i）长期炎症的细胞和分子特征是什么？ (ii) 哪些靶点调节体内反应。 具体目标 1 将检验以下假设：长期炎症会诱发显着的病理生理反应，其特征可以通过监测基因表达和代谢通量的动态变化来表征。 具体目标 2 将检验以下假设：先进的生物信息学方法可以识别炎症反应控制的关键点。 具体目标 3 将检验这样的假设：代谢亢进反应可以通过干扰目标 2 中确定的关键控制点来调节。这些研究代表了一种综合方法，整合了基因表达数据以及代谢亢进发生和维持期间获得的代谢通量水平。已经组建了一个研究小组，汇集了烧伤动物模型和代谢亢进（Berthiaume）、分子生物工程（Roth）、代谢工程（Ierapetritou）和生物信息学（Androulakis）方面的关键专业知识 公共健康相关性：该提案旨在利用从动物（大鼠）模型收集的数据来了解烧伤败血症诱发炎症的高代谢反应的控制机制。我们的最终目标是了解我们努力的系统反应，最终建议改进严重烧伤康复的治疗策略。