Regulation of Arginase Genes in Sepsis and Trauma

脓毒症和创伤中精氨酸酶基因的调节

• 批准号: 6911513
• 负责人: SIDNEY MACHEN MORRIS
• 金额: $ 24.71万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6911513
• 关键词: aminoacid metabolism; antiinflammatory agents; arginase; arginine; bacteria infection mechanism; bacterial disease; bacterial genetics; blood toxicology; cyclic AMP; gel mobility shift assay; gene expression; genetic promoter element; genetic regulation; genetic transcription; interleukin 4; lipopolysaccharides; messenger RNA; nitric oxide; nitric oxide synthase; polymerase chain reaction; transcription factor; transforming growth factors; trauma

Sepsis, traumatic injury, injury complicated by infection, and major surgery all initiate systemic responses that follow release of complex and varied combinations of cytokines and stress hormones, as well as of bacterial endotoxins in infection. In extreme conditions, these responses can result in death due to organ dysfunction and multiple organ failure. Major changes in arginine metabolism are major hallmarks of these pathophysiologic states. These changes include dramatic increases in expression of the arginases (isoforms I and I1), which can have a significant impact not only on NO synthesis but also on synthesis of polyamines and proline, which are involved in cell proliferation and wound healing. We have shown that transcription of the arginase genes exhibits a complex pattern of responses to a wide variety of pro- and anti-inflammatory stimuli. It is particularly notable that responses of the arginases and iNOS to these stimuli are not identical. A clear understanding of the complex changes in arginine metabolism, as well as of the mechanisms underlying the responses to the complex combinations of pro- and anti-inflammatory cytokines and other agents, is essential for advances in the prevention or reversal of multiple organ failure. To elucidate these mechanisms, we propose the following aims: AIM I. To define the promoter elements and cognate transcription factors responsible for regulation of the arginase I gene-by pro- and anti-inflammatory agents. AIM II. To define the promoter elements and cognate transcription factors responsible for regulation of the arginase II gene by pro- and anti-inflammatory agents. AIM III. To define mechanisms involved in regulation of arginase II mRNA stability. In each of these aims, we will test specific hypotheses regarding transcriptional regulation of the arginase genes by individual stimuli and combinations thereof. Elucidation of the mechanisms involved in regulation of arginase gene expression, combined with independent efforts by others to elucidate the mechanisms involved in regulation of the iNOS gene, will greatly enhance our understanding of the molecular events underlying the pathophysiology of sepsis and trauma and thus aid in design of therapeutic strategies for these disease states.

脓毒症、创伤性损伤、感染并发损伤和大手术都会引发全身反应，这些反应是在感染时释放复杂多样的细胞因子和应激激素组合以及细菌内毒素后产生的。 在极端条件下，这些反应可能会因器官功能障碍和多器官衰竭而导致死亡。 精氨酸代谢的重大变化是这些病理生理状态的主要标志。 这些变化包括精氨酸酶（亚型 I 和 I1）表达的急剧增加，这不仅对 NO 合成产生显着影响，而且对参与细胞增殖和伤口愈合的多胺和脯氨酸的合成产生显着影响。 我们已经证明，精氨酸酶基因的转录对多种促炎和抗炎刺激表现出复杂的反应模式。 特别值得注意的是，精氨酸酶和 iNOS 对这些刺激的反应并不相同。 清楚地了解精氨酸代谢的复杂变化，以及促炎和抗炎细胞因子及其他药物的复杂组合的反应机制，对于预防或逆转多器官衰竭的进展至关重要。 为了阐明这些机制，我们提出以下目标： 目的 I. 定义负责通过促炎剂和抗炎剂调节精氨酸酶 I 基因的启动子元件和同源转录因子。 目标二。定义负责促炎剂和抗炎剂调节精氨酸酶 II 基因的启动子元件和同源转录因子。 目标三。定义参与精氨酸酶 II mRNA 稳定性调节的机制。在每个目标中，我们将测试有关通过单独刺激及其组合对精氨酸酶基因进行转录调节的具体假设。 阐明参与精氨酸酶基因表达调控的机制，结合其他人独立努力阐明参与 iNOS 基因调控的机制，将极大地增强我们对脓毒症和创伤病理生理学基础分子事件的理解，从而有助于设计针对这些疾病状态的治疗策略。