Bioinformatics Analysis of Control Mechanisms of Hypermetabolism

描述(申请人提供)：火灾和烧伤是最常见的意外伤害死亡原因之一。在美国，每年有近120万人报告烧伤受伤，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和继发性获得性感染的影响将对烧伤患者的住院、医疗、治疗和生存产生深远的影响。严重的热损伤与高代谢和分解代谢有关。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失控和长期作用。炎症反应的程度已被证明与存活率呈负相关。研究表明，钝化过度的炎症信号级联反应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)什么靶点调节体内的反应。 具体目标1将检验这一假说，即长期炎症可引起显着的病理生理反应，其特征是监测基因表达和代谢通量的动态变化。 《特定目标2》将检验这一假设，即先进的生物信息学方法可以识别炎症反应的控制点。 特定目标3将测试高代谢反应可以通过干扰目标2中确定的控制点来调节的假设。这些研究代表了一种综合的方法，整合了在高代谢开始和维持期间获得的基因表达和代谢通量水平的数据。已经组建了一个研究小组，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(Andreulakis)方面的关键专业知识。 公共卫生相关性：这项建议旨在利用从动物(大鼠)模型收集的数据来理解烧伤-脓毒症引起的炎症的高代谢反应的控制机制。我们的最终目标是了解全身反应，最终提出改善严重烧伤康复治疗策略的建议。

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.