NUTRITION, CYTOKINES, AND ANABOLIC SIGNALING MECHANISMS

营养、细胞因子和合成代谢信号机制

• 批准号: 2518502
• 负责人: ROBERT J SMITH
• 金额: $ 23.46万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-01 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2518502
• 关键词: androgen analog; fasting; insulin sensitivity /resistance; insulinlike growth factor; laboratory rabbit; laboratory rat; nutrition related tag; phosphorylation; protein tyrosine kinase; protein tyrosine phosphatase; somatotropin; tumor necrosis factor alpha; tyrosine

Patients with severe illnesses of diverse etiologies, including trauma, infections, burn injuries, major surgery, and certain cancers, frequently develop a catabolic response that contributes to disease morbidity and complications, delays recovery, and may affect final disease outcome. Intensive nutrition support has significant benefit in catabolic patients, but current methods of nutrition support often are not effective in reversing the catabolic state. In these patients, resistance to the actions of anabolic hormones, including insulin, growth hormone, and possibly the growth factor IGF-I, appears to be a significant contributing factor to the catabolic response. In considering the causes of anabolic hormone resistance, as well as the causes of the overall catabolic response, current evidence suggests important roles for both nutrient depletion and cytokines, such as tumor necrosis factor alpha (TNFalpha). Recent data indicate that protein tyrosine phosphorylation reactions are involved in the cellular actions of insulin, growth hormone, and IGF-I, and that TNFalpha inhibits hormone-stimulated tyrosine phosphorylation. The objectives of this project are to investigate the role of altered tyrosine phosphorylation and other signaling reactions in catabolic states by studying: [1] the molecular mechanisms through which nutrient depletion causes or contributes to anabolic hormone resistance, [2] the molecular basis for TNFalpha-induced anabolic hormone resistance, [3] the interrelationships between the effects of nutrient depletion and the actions of TNFalpha, and [4] a new approach to treating the catabolic response by augmenting tyrosine phosphorylation-related signaling. Novel experimental methods developed in the Principal Investigator's laboratory for the investigation of molecular signaling events in the tissues of intact laboratory rats, using specific antibodies and cDNA probes to isolate and quantify hormone pathway intermediates, will be applied to studies on the effects of nutrient deprivation and TNFalpha administration on anabolic hormone action. This experimental approach will be made possible through the collaborative efforts of the Principal Investigator, with his expertise in nutritional molecular biology and biochemistry, and two Co- investigators, with expertise in nutrition, cytokines, and specialized methods required for intact animal studies. The work will investigate fundamental molecular mechanisms of the catabolic response in pathophysiologically relevant experimental models with the ultimate goal of developing new approaches to the use of nutritional, hormonal, and pharmacological interventions in the treatment of catabolic patients.

患有多种病因的严重疾病的患者，包括创伤、 感染、烧伤、大手术和某些癌症，经常 产生导致疾病发病率的分解代谢反应， 并发症，延迟康复，并可能影响最终的疾病结果。 强化营养支持对分解代谢有显着益处 患者，但目前的营养支持方法往往不能 有效逆转分解代谢状态。在这些患者中，抵抗力 合成代谢激素的作用，包括胰岛素、生长激素、 可能还有生长因子 IGF-I，似乎是一个重要的因素 分解代谢反应的影响因素。在考虑原因时 合成代谢激素抵抗的情况，以及总体的原因 分解代谢反应，目前的证据表明两者的重要作用 营养耗尽和细胞因子，例如肿瘤坏死因子α （肿瘤坏死因子α）。最近的数据表明蛋白质酪氨酸磷酸化 反应涉及胰岛素的细胞作用、生长 激素和 IGF-I，并且 TNFα 抑制激素刺激 酪氨酸磷酸化。该项目的目标是 研究改变酪氨酸磷酸化的作用和其他 分解代谢状态下的信号反应通过研究：[1] 分子 营养消耗导致或促成的机制 合成代谢激素抵抗，[2] TNFα 诱导的分子基础 合成代谢激素抵抗，[3] 之间的相互关系 营养耗尽的影响和 TNFα 的作用，以及 [4] 一种新的 通过增加酪氨酸来治疗分解代谢反应的方法 磷酸化相关信号传导。开发新的实验方法 在首席研究员的实验室进行调查 完整实验室大鼠组织中的分子信号传导事件， 使用特异性抗体和 cDNA 探针来分离和定量激素 途径中间体，将应用于研究 营养剥夺和 TNFα 施用对合成代谢激素的影响 行动。这种实验方法将通过 首席研究员以其专业知识的协作努力 营养分子生物学和生物化学，以及两个共同 具有营养、细胞因子和专业知识的研究人员 完整动物研究所需的方法。工作将进行调查 分解代谢反应的基本分子机制 具有最终目标的病理生理学相关实验模型 开发使用营养、激素和药物的新方法 治疗分解代谢患者的药物干预。