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: 6547471
• 负责人: SIDNEY MACHEN MORRIS
• 金额: $ 26.81万
• 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 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6547471
• 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.

败血症，创伤性损伤，因感染而复杂的损伤以及大手术均启动全身反应，这些反应随后释放了细胞因子和应激激素的复杂和多样组合，以及感染中细菌内毒素的组合。 在极端条件下，这些反应可能导致器官功能障碍和多器官衰竭导致死亡。 精氨酸代谢的主要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（同工型I和I1）的表达急剧增加，这不仅对无合成，而且对多胺和脯氨酸的合成产生重大影响，这些胺和脯氨酸与细胞增殖和伤口愈合有关。 我们已经表明，精氨酸酶基因的转录表现出对多种促和抗炎刺激的复杂响应模式。 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。 对精氨酸代谢的复杂变化以及对促抗炎和抗炎细胞因子和其他药物的复杂组合的响应的基础机制的清晰了解对于预防或逆转多器官衰竭的进步至关重要。 为了阐明这些机制，我们提出了以下目的：目标I。定义启动子元素和认知转录因子负责调节精氨酸酶I基因和抗炎药。 目标II。定义促启动子元素和同源转录因子，负责通过促炎和抗炎剂调节精氨酸酶II基因的调节。 目标三。定义与精氨酸酶II mRNA稳定性调节的机制。在这些目标中的每一个中，我们将通过单个刺激及其组合来检验有关精氨酸基因转录调节的特定假设。 阐明精氨酸酶基因表达所涉及的机制，再加上其他人在阐明INOS基因调节的机制方面的独立努力，将极大地增强我们对屈服和创伤病理学基础的分子事件的理解，从而有助于这些疾病状态的治疗策略的设计。