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: 7679521
• 负责人: IOANNIS P ANDROULAKIS
• 金额: $ 31.4万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7679521
• 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。在美国，每年报告几乎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率和死亡率的主要原因。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。严重的热损伤与高代谢和catalysis有关。由于尚不清楚的原因，严重烧伤和创伤可导致促炎细胞因子的不受控制和延长的作用。炎症反应的程度已被证明与生存率呈负相关。研究表明，钝化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）什么靶点调节体内反应。 具体目标1将检验这一假设，即长期炎症诱导显著的病理生理反应，其特征在于监测基因表达和代谢通量的动态变化。 具体目标2将测试先进的生物信息学方法可以识别炎症反应控制的关键点的假设。 具体目标3将检验以下假设：高代谢反应可以通过干扰目标2中确定的控制临界点来调节。这些研究代表了一种综合方法，整合了基因表达数据，以及在高代谢发作和维持期间获得的代谢通量水平。已组建一支调查团队，汇集了烧伤动物模型和高代谢（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 公共卫生关系：本研究旨在通过动物（大鼠）模型研究烧伤脓毒症引起炎症反应的高代谢反应的调控机制。我们的最终目标是了解我们努力的全身反应，最终提出改善严重烧伤恢复的治疗策略。