Inflammation in Sickle Disease

镰状病的炎症

• 批准号: 7098220
• 负责人: Gregory M Vercellotti
• 金额: $ 37.38万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7098220
• 关键词: bilirubin; blood vessel occlusion; carbon monoxide; chemotherapy; disease /disorder model; enzyme mechanism; ferritin; free radical oxygen; gene induction /repression; gene targeting; gene therapy; genetically modified animals; heme oxygenase; hemolysis; hypoxia; inflammation; laboratory mouse; nonhuman therapy evaluation; nuclear factor kappa beta; oxygen transport; pathologic process; selectins; sickle cell anemia; vascular endothelium

DESCRIPTION (provided by applicant): Sickle cell disease (SCD) is a devastating hemolytic disease characterized by recurring episodes of painful vaso-occlusion, leading to ischemia-reperfusion injury and organ damage. Despite significant advances in the knowledge of sickle hemoglobin and red blood cells, we still lack a clear understanding of the pathophysiology and treatment of vaso-occlusion. It is now understood that oxidative stress is a trigger for vascular inflammation which promotes vaso-occlusion. Recently the critical roles of endothelial cell activation and inflammation in vaso-occlusion have been recognized, in part due to the development of transgenic murine models of SCD. However, a critical gap exists in explaining how does the sickle patient defend or adapt to excessive hemolysis with the release of hemoglobin/heme/iron into the vasculature and the exuberant production of reactive oxygen species. To remove this heme burden and lessen the oxidative stress, the vasculature increases the expression of heme oxygenase-1 (HO-1). HO-1 is a highly adaptable anti-inflammatory defense against excessive heme burdens. We hypothesize that HO-1, an adaptive, anti- inflammatory gene, plays a critical role in the inhibition and resolution of vaso-occlusion in SCD. In Specific Aim 1, we will test whether HO-1 and its downstream products, including carbon monoxide, biliverdin/bilirubin and ferritin, manipulated pharmacologically or with gene therapy, will prevent hypoxia/reoxygenation-induced stasis, ameliorate organ pathology and prolong life span in transgenic sickle mice. In Specific Aim 2, we will identify the mechanisms whereby HO-1 modulates SCD in SCD by examining the effects of HO-1 and its products on oxidative stress, NF-kB activation and endothelial cell adhesion molecule expression. We will demonstrate that adaptative increases in HO-1 activity in SCD are inadequate to handle the excessive heme burden. We expect that further upregulation of HO-1 activity and/or its downstream products will be important strategies to develop innovative new therapies to prevent and treat vaso-occlusion in SCD. This research on inflammation using mouse models of sickle cell anemia wilt identify new targets for drug therapies to alleviate the complications of SCD. These new treatments should decrease sickle crises, prevent organ damage, improve quality and length of lives of sickle cell anemia patients.

描述（由申请人提供）：镰状细胞疾病（SCD）是一种毁灭性的溶血疾病，其特征是经常发生的疼痛的血管cl缝发作，导致缺血 - 重新灌注损伤和器官损伤。尽管了解镰状血红蛋白和红细胞的知识取得了重大进步，但我们仍然对血管肠结已病理生理学和治疗缺乏清晰的了解。现在可以理解，氧化应激是促进血管cl牙的血管炎症的触发。最近，内皮细胞活化和炎症在血管cl缝体中的关键作用已被识别，部分原因是SCD的转基因鼠模型的发展。然而，在解释镰刀患者如何捍卫或适应过度溶血的情况下，存在血红蛋白/血红素/铁中的过度溶血，并存在一个关键的差距。为了消除这种血红素负担并减轻氧化应激，脉管系统增加了血红素氧酶-1（HO-1）的表达。 HO-1是针对过度血红素负担的高度适应性抗炎防御。我们假设HO-1是一种自适应，抗炎性基因，在SCD中的血管批准的抑制和分辨率中起着至关重要的作用。在特定目标1中，我们将测试HO-1及其下游产品，包括一氧化碳，双脂蛋白/胆红素和铁蛋白，在药理学上进行操纵或进行基因治疗是否会防止缺氧/再氧诱导的持续性降低诱导的持续性，降低了细胞器官的病理，并且在跨基因的小心小鼠中延长了生命。在特定目标2中，我们将通过检查HO-1及其产物对氧化应激，NF-KB激活和内皮细胞粘附分子表达的影响来确定HO-1在SCD中调节SCD的机制。我们将证明SCD中HO-1活性的适应性增加是不足以应付过多的血红素负担。我们预计，HO-1活动和/或其下游产品的进一步上调将是开发创新的新疗法的重要策略，以预防和治疗SCD中的血管结合。这项使用镰状细胞贫血小鼠模型对炎症的研究确定了药物疗法的新靶标，以减轻SCD并发症。这些新疗法应减少镰状危机，防止器官损害，改善镰状细胞贫血患者的质量和寿命。