Effects of Statins on Endometrial Stoma

他汀类药物对子宫内膜造口的影响

• 批准号: 7318135
• 负责人: Antoni J Duleba
• 金额: $ 28.26万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7318135
• 关键词: Affect; Age; Antioxidants; Apoptosis; Benign; Clinical; Condition; Data; Depth; Development; Endometrial; Endometrial Stromal Cell; Generations; Gland; Growth; Gynecologic; Implant; Inflammation; Inflammatory; Lead; Monomeric GTP-Binding Proteins; NADPH Oxidase; Oxidative Stress; Pathway interactions; Phosphorylation; Protein Isoprenylation; Reaction; Research; Role; Signal Transduction Pathway; Stomas; Tissues; Vascular Smooth Muscle; Woman; base; endometrial stroma; endometriosis; in vivo; insight; isoprenylation; mevalonate; mouse model; novel; reproductive; rho

Endometriosis is one of the most common benign gynecologic conditions affecting women of reproductive age. Formation of endometriotic implants requires ectopic attachment and proliferation of endometrial stroma and glands. Prominent features of endometriosis include inflammatory reaction and increased oxidative stress. We propose a novel hypothesis that inhibition of the mevalonate pathway by statins will inhibit growth of endometrial stroma and endometriotic implants as well as decrease oxidative stress. Specifically, we postulate that statins affect endometrial stromal cells by: (i) inhibiting isoprenylation of proteins, especially small GTPases such as Ras and Rho leading to modulation of signal transduction pathways regulating growth, and (ii) decreasing generation of reactive oxigen species, which also affect growth. This underlying hypothesis is based on evidence that in several tissues, such as vascular smooth muscle, products of the mevalonate pathway facilitate isoprenylation of small GPTases and thus activate signal transduction pathways promoting growth. In vascular smooth muscle and in several other tissues, inhibition of the mevalonate pathway by statins inhibits growth and exerts antioxidant effects. Our preliminary studies have shown that moderate oxidative stress stimulates endometrial stromal proliferation. Furthermore, our preliminary data indicate that statins inhibit endometrial stromal proliferation, while blocking ERK1/2 phosphorylation. The specific aims of this proposal are to study in depth the effects of statins on growth and oxidative stress: (i) in endometrial stromal cells and (ii) in endometriotic implants in a nude mouse model. These studies will provide new insight into the mechanisms regulating growth and function of endometrial tissues. Ultimately, the proposed research may lead to the development of new treatements of endometriosis, such as clinical use of statins.

子宫内膜异位症是影响女性生殖功能的最常见的良性妇科疾病之一