Reactive Oxygen Species Regulate Smooth Muscle Growth*

描述（由申请人提供）：子宫平滑肌瘤或肌瘤是女性最常见的盆腔肿瘤，也是美国子宫切除术的主要指征。非裔美国妇女的症状性平滑肌瘤发病率是其他群体的3-6倍。虽然这种发病率增加可能有遗传因素，但我们相信其他因素也可能起作用。非裔美国人高血压、肥胖和糖尿病的发病率有所增加。研究表明，高血压或肥胖患者血液中升高的血管紧张素II、血清素和油酸等因子对血管平滑肌细胞（SMCs）在损伤反应中的增殖和基质生成有显著影响。这些因子与生长因子一起，通过涉及活性氧（ROS）产生的信号通路调节SMCs的生长和分化。我们假设类似的ros依赖机制参与了平滑肌瘤SMCs的调节。本建议的具体目的是：1。确定ROS是否是平滑肌瘤SMCs中EGF和PDGF信号通路的关键组成部分。2. 确定血管紧张素II、血清素和油酸是否调节平滑肌瘤SMCs的增殖和细胞外基质的产生，并确定这些分子是否通过其自身受体和/或通过反激活EGF或PDGF受体起作用。我们还将确定ROS在这两种激活途径中的作用。3. 目的：确定halofuginone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平滑肌瘤SMCs的增殖和胶原生成。氟化酮在平滑肌瘤动物模型中的疗效也将被评估。本提案的总体目标是阐明ROS在调节平滑肌瘤SMCs生长和分化的信号通路中的作用。抑制ROS产生或抑制ROS下游靶点的分子可能被证明是治疗平滑肌瘤的有用治疗剂。Halofuginorle已被证明可以抑制血管成形术大鼠血管SMCs的新内膜形成和裸鼠肿瘤形成。我们认为halofuginone可能通过抑制这些细胞以及平滑肌瘤SMCs中ros依赖的信号通路而起作用。

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.