GENETIC REGULATION OF CELLULAR ENERGETICS DURING INITIAL ILLNESS

疾病初期细胞能量的遗传调节

• 批准号: 6240629
• 负责人: Danny O. Jacobs
• 金额: $ 21.47万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 1998-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6240629
• 关键词: adenosine diphosphate; adenosine triphosphate; adenosinetriphosphatase; bacterial disease; bioenergetics; blood toxicology; body water; complement; creatine phosphate; electrolytes; enzyme activity; injury; laboratory rat; monoclonal antibody; nuclear magnetic resonance spectroscopy; phosphorylation; sodium channel; tumor necrosis factor alpha

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.

能量产生抑制和组织能量储存耗尽 通常伴随着败血症和创伤性能量需求的增加 受伤。 然而，这些事件的始作俑者和调解者，究竟 能量不足的性质、异常首次发生的时间以及 它们的意义尚不清楚。 该提案旨在审查 补体激活、细胞因子产生和自由基的作用 细胞生物能量学变化的形成， 细胞内 pH 值以及体内钠和水的分布。 在动物中 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 补体活性、细胞因子精细化和细胞能量学； 2） 补体或细胞因子活性如何改变 ATP 和磷酸肌酸 骨骼肌中的利用、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发的 通过膜通道； 4）是否针对特定治疗 补体或细胞因子将以某种方式增强生存 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 光谱 (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 磁化传递技术和MRS-可见磷酸盐水空间 标记。 体内 MRS 还将用于检查体内代谢变化 运动和恢复过程中骨骼肌缺血和灌注， 测量细胞能量状态的变化，并定量 ATP 周转率。 体内能量状态指标将包括磷酸化 电位、游离 ADP 浓度和 ATP 的自由能水解。 实验干预将用于理解机制 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结果将加深我们对 应激和损伤期间能量代谢的调节。