Reactive Oxygen Species Regulate Smooth Muscle Growth

活性氧调节平滑肌生长

• 批准号: 7271158
• 负责人: Romana A. Nowak
• 金额: $ 29.01万
• 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 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7271158
• 关键词: Acids; African American; Angioplasty; Angiotensin II; Angiotensins; Animal Model; Atherosclerosis; Blood Circulation; Blood Vessels; Cell Proliferation; Cells; Collagen; Cytoskeleton; Diabetes Mellitus; Diagnosis; Differentiation and Growth; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Estradiol; Fibroblasts; Fibroid Tumor; Fibrosis; Genetic; Goals; Growth; Growth Factor; Growth Factor Receptors; Halofuginone; Hormones; Hypertension; Hysterectomy; Incidence; Kidney; Lead; Leiomyoma; Mitogens; Nude Mice; Obesity; Oleic Acid; Oleic Acids; Ovarian Steroid Hormone; Pathway interactions; Patients; Pelvic Neoplasms; Pelvis; Phosphotransferases; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor Receptor; Play; Production; Progesterone; Rate; Rattus; Reactive Oxygen Species; Regulation; Reporting; Role; Second Messenger Systems; Serotonin; Signal Pathway; Signaling Molecule; Smooth Muscle; Smooth Muscle Myocytes; Testing; Therapeutic Agents; Time; Transactivation; Uterine Fibroids; Woman; Work; mesangial cell; receptor; research study; response; response to injury; second messenger; tumor

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（由申请人提供）：子宫肌瘤或纤维瘤是女性最常见的盆腔肿瘤，也是美国子宫切除术的主要适应症。非裔美国女性有症状的平滑肌瘤的发病率比其他群体高 3-6 倍。虽然发病率增加可能与遗传因素有关，但我们相信其他因素也可能发挥作用。非裔美国人高血压、肥胖症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 (SMC) 响应损伤时的增殖和基质生成具有显着影响。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 SMC 的生长和分化。我们假设类似的 ROS 依赖性机制参与了平滑肌瘤 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 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 受体发挥作用。我们还将确定 ROS 在这两种激活途径中的作用。 3.确定卤常酮是否通过抑制细胞内ROS的增加或ROS下游靶标之一来抑制生长因子刺激的平滑肌瘤SMC的增殖和胶原蛋白产生。还将评估卤常酮在平滑肌瘤动物模型中的功效。该提案的总体目标是阐明 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 产生或抑制 ROS 下游靶标的分子可能被证明是治疗平滑肌瘤的有用治疗剂。 Halofuginorle 已被证明可以抑制接受血管成形术的大鼠中血管 SMC 的新内膜形成和裸鼠中的肿瘤形成。我们相信，halofuginone 可能通过抑制这些细胞以及平滑肌瘤 SMC 中 ROS 依赖性信号通路发挥作用。

项目成果

The antifibrotic drug halofuginone inhibits proliferation and collagen production by human leiomyoma and myometrial smooth muscle cells.

• DOI: 10.1016/j.fertnstert.2008.11.018
• 发表时间: 2010-03-01
• 期刊: Fertility and sterility
• 影响因子: 6.7
• 作者: Grudzien MM;Low PS;Manning PC;Arredondo M;Belton RJ Jr;Nowak RA
• 通讯作者: Nowak RA