Reactive Oxygen Species Regulate Smooth Muscle Growth*

活性氧调节平滑肌生长*

• 批准号: 6805747
• 负责人: Romana A. Nowak
• 金额: $ 30.6万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-26 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6805747
• 关键词: African American; athymic mouse; biological signal transduction; cell differentiation; cell growth regulation; cell line; cell proliferation; collagen; epidermal growth factor; extracellular matrix; free radical oxygen; growth factor receptors; immunocytochemistry; leiomyoma; northern blottings; platelet derived growth factor; polymerase chain reaction; serotonin; smooth muscle; uterus

DESCRIPTION (provided by applicant): Uterine leiomyomas, or fibroids, are the most common pelvic tumors in women and are the primary indication for hysterectomy in the US. The incidence of symptomatic leiomyomas is 3-6 times higher in African American women than in other groups. While there may be a genetic component to this increased incidence we believe other factors may play a role. African-Americans show an increased incidence of hypertension, obesity and diabetes. Studies have shown that factors such as angiotensin II, serotonin and oleic acid, which are elevated in the bloodstream of patients with hypertension or obesity, have significant effects on proliferation and matrix production by vascular smooth muscle cells (SMCs) in response to injury. These factors, along with growth factors, regulate growth and differentiation of SMCs via a signaling pathway involving the production of reactive oxygen species (ROS). We hypothesize that similar ROS-dependent mechanisms are involved in the regulation of leiomyoma SMCs. The specific aims of this proposal are: 1. To determine whether ROS are a critical component of the EGF and PDGF signalling pathways in leiomyoma SMCs. 2. To determine whether angiotensin II, serotonin and oleic acid regulate proliferation and extra-cellular matrix production by leiomyoma SMCs and to determine whether these molecules act through their own receptors and/or by transactivating EGF or PDGF receptors. We will also determine the role of ROS in both of these activation pathways. 3. To determine whether halofuginone inhibits growth factor-stimulated proliferation and collagen production by leiomyoma SMCs by either inhibiting the increase in intracellular ROS or one of the downstream targets of ROS. The efficacy of halofuginone in an animal model of leiomyomas will also be assessed. The overall goal of this proposal is to elucidate the role of ROS in the signaling pathways that regulate growth and differentiation of leiomyoma SMCs. Molecules that inhibit ROS production or inhibit downstream targets of ROS may prove to be useful therapeutic agents for the treatment of leiomyomas. Halofuginorle has been shown to inhibit neointimal formation by vascular SMCs in rats undergoing angioplasty and tumor formation in nude mice. We believe halofuginone may act by inhibiting ROS-dependent signaling pathways in these cells as well as in leiomyoma SMCs.

描述(申请人提供)：子宫肌瘤，或肌瘤，是最常见的女性盆腔肿瘤，也是美国子宫切除术的主要适应症。非洲裔美国女性的症状性肌瘤发病率是其他群体的3-6倍。虽然这种增加的发病率可能有遗传因素，但我们认为其他因素也可能起到作用。非洲裔美国人表现出高血压、肥胖症和糖尿病的发病率增加。研究表明，血管紧张素II、5-羟色胺和油酸等因子在高血压或肥胖症患者的血液中升高，对血管平滑肌细胞(SMCs)在损伤时的增殖和基质产生有显著影响。这些因子与生长因子一起，通过产生活性氧(ROS)的信号通路调节SMC的生长和分化。我们假设，类似的ROS依赖机制也参与了对肌瘤SMC的调节。本研究的具体目的是：1.确定ROS是否是子宫肌瘤SMC中EGF和PDGF信号通路的重要组成部分。2.确定血管紧张素II、5-羟色胺和油酸是否调节子宫肌瘤SMC的增殖和细胞外基质的产生，以及这些分子是否通过各自的受体和/或反式激活EGF或PDGF受体发挥作用。我们还将确定ROS在这两条激活途径中的作用。3.确定是否通过抑制细胞内ROS的增加或ROS的下游靶点之一来抑制生长因子刺激的子宫肌瘤SMC的增殖和胶原的产生。在子宫肌瘤动物模型中，也将评估常青藤酮的疗效。这项建议的总体目标是阐明ROS在调节平滑肌瘤SMC生长和分化的信号通路中的作用。抑制ROS产生的分子或抑制ROS下游靶点的分子可能被证明是治疗肌瘤的有用的治疗剂。已有研究表明，在接受血管成形术的大鼠血管内膜细胞和裸鼠体内的肿瘤形成过程中，Halofugiorle能抑制新生内膜的形成。我们相信，在这些细胞中，以及在子宫肌瘤的SMC中，常青藤酮可能通过抑制ROS依赖的信号通路发挥作用。