GENETIC REGULATION OF CELLULAR ENERGETICS DURING INITIAL ILLNESS

能量产生的抑制和组织能量储存的消耗 通常伴随脓毒症和创伤性的能量需求增加 损伤 然而，这些事件的发起者和调解者，确切的 能量不足的性质，首次出现异常的时间， 其意义尚不清楚。 这项建议旨在审查 补体激活、细胞因子产生和自由基的作用 在细胞生物能量学变化的起源中形成， 细胞内pH以及体内钠和水分布。 在动物 脓毒症、缺血/再灌注和全身炎症模型， 实验旨在确定：1）变化之间的关系 在补体活性、细胞因子加工和细胞能量学方面; 2） 补体或细胞因子活性如何改变ATP和磷酸肌酸 利用，糖酵解和糖原分解; 3）是否 能量代谢的变化是由钠的流入引起的 通过膜通道;以及4）是否针对 补体或细胞因子将以一种可以 与改善能源状况有关。 水和钠的变化 将使用体内磁共振测量分布 波谱（MRS）、MRS-可见水空间标记和钠位移 试剂. 将使用MRS测量磷酸肌酸分解率 磁化转移技术和MRS可见膦酸盐水空间 标记。 体内MRS也将用于检查代谢变化， 缺血和灌注骨骼肌在运动和恢复过程中， 测量细胞能量状态的变化，并定量ATP的周转。 体内能量状态的指标将包括磷酸化 电位、游离ADP浓度和ATP水解自由能。 实验干预将用于了解机制 观察到的变化包括使用单克隆抗体， TNF和其他细胞因子，以及补体阻断。 结果 从这些实验中获得的信息将提高我们对 在应激和损伤过程中调节能量代谢。

Depression of energy production and depletion of tissue energy stores typically accompany the increased energy demands of sepsis and traumatic injury. However, the initiators and mediators of these events, the exact nature of the energy deficits, the times when abnormalities first occur and their significance are unclear. This proposal is designed to examine the role of complement activation, cytokine production and free radical formation in the genesis of changes in cellular bioenergetics, intracellular pH, and sodium and water distribution in vivo. In animal models of sepsis, ischemia/reperfusion, and systemic inflammation, experiments are designed to determine: 1) the relationship between changes in complement activity, cytokine elaboration, and cellular energetics; 2) how complement or cytokine activity modify ATP and phosphocreatine utilization, glycolysis and glycogenolysis in skeletal muscle; 3) whether the changes in energy metabolism are initiated by the influx of sodium though membrane channels; and 4) whether specific therapy directed against complement or cytokines will enhance survival in a manner that can be related to improved energy status. Changes in water and sodium distribution will be measured using in vivo magnetic resonance spectroscopy (MRS), MRS-visible water space markers, and sodium shift reagent. Phosphocreatine breakdown rates will be measured using MRS magnetization transfer techniques and MRS-visible phosphonate water space markers. In vivo MRS will also be used to examine metabolic changes in ischemic and perfused skeletal muscle during exercise and recovery, to measure changes in the cell's energy state, and to quantitate ATP turnover. Indices of energy status in vivo will include the phosphorylation potential, free ADP concentration and the free energy hydrolysis of ATP. Experimental interventions what will be used to understand the mechanisms of the observed changes include the use of monoclonal antibodies against TNF and other cytokines, and well as complement blockade. The results obtained from these experiments would improve our understanding of the regulation of energy metabolism during stress and injury.