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，在美国是子宫切除术的主要适应症。有症状的平滑肌瘤的发病率在非洲裔美国妇女比其他群体高3-6倍。虽然这种发病率的增加可能有遗传因素，但我们认为其他因素也可能起作用。非裔美国人显示高血压、肥胖和糖尿病的发病率增加。研究表明，高血压或肥胖患者血流中升高的血管紧张素II、5-羟色胺和油酸等因子对血管平滑肌细胞（SMC）响应损伤的增殖和基质产生具有显著影响。这些因子沿着生长因子，通过涉及活性氧（ROS）产生的信号传导途径调节SMC的生长和分化。我们推测，类似的ROS依赖性机制参与平滑肌瘤SMC的调节。该提案的具体目标是：1.确定ROS是否是平滑肌瘤SMC中EGF和PDGF信号通路的关键组分。2.确定血管紧张素II、5-羟色胺和油酸是否调节平滑肌瘤SMC的增殖和细胞外基质产生，并确定这些分子是否通过其自身受体和/或通过反式激活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.确定常山酮是否通过抑制细胞内ROS或ROS下游靶点之一的增加来抑制平滑肌瘤SMC的生长因子刺激的增殖和胶原蛋白产生。还将评估常山酮在平滑肌瘤动物模型中的功效。本研究的总体目标是阐明活性氧在平滑肌瘤平滑肌细胞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用于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平滑肌细胞的新生内膜形成和裸鼠肿瘤形成。我们认为常山酮可能通过抑制这些细胞以及平滑肌瘤SMC中的ROS依赖性信号通路发挥作用。

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.