Mevalonate pathway and thecal-interstitial function

描述（申请人提供）：适当的卵巢发育和功能需要调节卵巢间质细胞生长和类固醇生成的机制。在病理条件下，如多囊卵巢综合征（PCOS），膜间质室增生，产生过多的雄激素。本研究旨在验证甲羟戊酸途径在调节卵巢膜间质细胞生长和功能中发挥重要作用的新假设。我们假设甲羟戊酸途径通过以下途径影响间质细胞：(i)改变小gtp酶如Ras和Rho的异戊二烯化，从而影响调节生长的信号转导途径；（ii）调节类固醇生成底物的可用性；（iii）改变氧化应激水平，从而影响生长和类固醇生成。最后，我们提出，抑制甲羟戊酸途径的药物，如他汀类药物，可能纠正多囊卵巢综合征的主要特征，包括膜间质细胞的过度生长，过多的雄激素产生和氧化应激。这一假设基于以下证据：在一些组织中，如血管平滑肌，甲羟戊酸途径的产物促进小gtpase的异戊二烯化，从而激活促进生长的信号转导途径。在血管平滑肌和其他一些组织中，他汀类药物抑制甲羟戊酸途径可抑制生长，发挥抗氧化作用并降低胆固醇合成。我们的初步研究表明，适度的氧化应激增加，他汀类药物通过阻断ERK1/2磷酸化抑制细胞膜间质细胞的增殖和甾体生成。我们还完成了一项试点临床试验，我们发现辛伐他汀可以降低多囊卵巢综合征女性的睾酮和黄体生成素。本提案的具体目的是深入研究甲羟戊酸途径在细胞膜间质细胞中的作用：(i)生长，（ii）类固醇生成和（iii）氧化应激。这些目标将通过对大鼠和人间质细胞培养的实验来解决。这些研究结果将为甲羟戊酸途径在卵巢间质生长和功能中的作用提供新的认识。最终，本研究可能为多囊卵巢综合征的病理生理学提供新的线索，并为开发新的治疗方法提供动力，如临床使用他汀类药物。

DESCRIPTION (provided by applicant): Appropriate ovarian development and function require mechanisms regulating growth and steroidogenesis of theca-interstitial cells. Under pathological conditions such as polycystic ovary syndrome (PCOS), theca-interstitial compartment is hyperplastic and produces excessive amounts of androgens. This proposal is designed to test the novel hypothesis that the mevalonate pathway plays an important role in modulation of growth and function of the ovarian theca-interstitial cells. We postulate that mevalonate pathway affects theca-interstitial cells by: (i) altering isoprenylation of small GTPases such as Ras and Rho affecting thus signal transduction pathways regulating growth, (ii) modulating the availability of substrates for steroidogenesis, and (iii) altering the level of oxidative stress, which, in turn, affects growth and steroidogenesis. Ultimately, we propose that, inhibition of the mevalonate pathway by agents such as statins may correct major features of PCOS including excessive growth of theca-interstitial cells, excessive androgen production and oxidative stress. This hypothesis is based on evidence that in several tissues, such as vascular smooth muscle, products of the mevalonate pathway facilitate isoprenylation of small GTPases 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, exerts antioxidant effects and decreases cholesterol synthesis. Our preliminary studies have shown that moderate oxidative stress increases and statins inhibit proliferation and steroidogenesis of theca-interstitial cells while blocking ERK1/2 phosphorylation. We have also completed a pilot clinical trial and we found that simvastatin decreases testosterone and luteinizing hormone in women with PCOS. The specific aims of this proposal are to study in depth the role of the mevalonate pathway in theca-interstitial cells on: (i) growth, (ii) steroidogenesis and (iii) oxidative stress. These aims will be addressed by experiments on rat and human theca-interstitial cell cultures. The results of these studies will provide a new insight into the role of mevalonate pathway on the growth and function of ovarian mesenchyme. Ultimately, the proposed research may shed new light on the pathophysiology of PCOS and provide an impetus towards the development of new therapeutic approaches, such as clinical use of statins.