Estrogen-neuroprotection due to astroglial Glu transporters occurs via TFG-a/bl

摘要 我们研究的长期目标是阐明17 E-E2的神经保护机制， 选择性雌激素受体调节剂（SERM），并开发发现合适的SERM的策略 可以用作神经保护剂，对女性没有癌症风险，对男性没有女性化效应。17 E- E2已被证明在各种神经退行性疾病中具有神经保护作用， 阿尔茨海默病（AD）和帕金森病（PD）。一些SERM，包括他莫昔芬（TX），也 在AD、PD和缺血的实验模型中具有神经保护特性。虽然 神经退行性变的机制尚不完全清楚，星形胶质细胞谷氨酸的损伤 已知转运蛋白在各种神经退行性疾病的发病机制中起关键作用，包括 AD和PD以及慢性锰暴露引起的锰中毒。Mn抑制 谷氨酸摄取和减少谷氨酸转运蛋白的表达，这是至关重要的调节细胞外 谷氨酸水平虽然E2似乎调节星形胶质细胞谷氨酸转运蛋白的表达，但其机制可能与E2的作用有关。 基本的E2监管仍然难以捉摸。此外，TX和其他SERM，其被认为是潜在的 由于它们对乳房的负面副作用的缺乏或减少， 子宫，不幸的是，还没有检查，以确定他们是否发挥潜在的有益 星形胶质细胞谷氨酸转运蛋白表达或活性的增强，这是该领域的一个缺陷，需要 寻址。为了弥补我们在这一重要领域的知识空白，我们将使用锰（Mnism） 作为受损的谷氨酸转运蛋白诱导的神经变性的实验模型，因为Mn处理是 已明确诱导与神经毒性相关的谷氨酸转运蛋白受损。我们的中央 假设是E2和TX可以通过以下方式逆转Mn诱导的谷氨酸转运体活性抑制： 转运蛋白运输的调节和雌激素受体（ER）依赖性表达， 通过调节生长因子，特别是转化生长因子的谷氨酸转运蛋白 （TGF）-D和TGF-E1。我们的总体假设将在以下具体目标中进行检验：1）E2/TX是否 通过增强谷氨酸转运蛋白的活性、表达和运输来逆转锰诱导的谷氨酸转运蛋白抑制。 2）E2/TX对谷氨酸转运体的作用是否依赖于ER亚型，3）TGF-β 1是否依赖于谷氨酸转运体， D和TGF-E1介导Mn诱导的谷氨酸转运体抑制的ER依赖性E2/TX逆转，4） E2/TX处理是否通过增强Mn诱导的神经毒性而导致体内神经保护 谷氨酸转运蛋白。我们的研究将提供新的见解的机制（S）的基础上， E2/TX在锰中毒模型中的神经保护作用，并将为锰中毒的新靶点提供潜在的见解。 治疗多种神经退行性疾病。

Abstract The long-term goal of our research is to elucidate the neuroprotective mechanisms of 17E-Estradiol (E2) and selective estrogen receptor modulators (SERMs) and develop strategies for the discovery of suitable SERMs that can be used as neuroprotectants without risks of cancer for women or of feminizing effects for men. 17E- Estradiol (E2) has been shown to be neuroprotective in various neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Some SERMs, including tamoxifen (TX), also possess neuroprotective properties in the experimental models of AD, PD and ischemia. Although the mechanisms involved in neurodegeneration are incompletely understood, impairment of astroglial glutamate transporters is known to play a key role in the pathogenesis of various neurodegenerative diseases, including AD and PD as well as manganism (Mnism) caused by chronic exposure to manganese (Mn). Mn inhibits glutamate uptake and decreases glutamate transporter expression, which is vital in regulating extracellular glutamate levels. Though E2 appears to regulate astroglial glutamate transporter expression, the mechanism underlying E2 regulation remains elusive. Furthermore, TX and other SERMs, which are considered potentially therapeutically advantageous over E2 due to their lack or diminished negative side effects on the breast and uterus, unfortunately have not been examined to determine whether they exert potentially beneficial enhancement of astroglial glutamate transporter expression or activity, a deficit in the field that needs addressing. To address these gaps in our knowledge in this important area, we will use Manganism (Mnism) as an experimental model for impaired glutamate transporter-induced neurodegeneration, as Mn treatment is well established to induce impairment of glutamate transporters associated with neurotoxicity. Our central hypothesis is that E2 and TX can reverse Mn-induced inhibition of glutamate transporter activities by both modulation of transporter trafficking and by estrogen receptor (ER)-dependent expression of glutamate transporters via modulation of growth factors, in particular transforming growth factors (TGF)-D and TGF-E1. Our overall hypothesis will be tested in the following specific aims: 1) whether E2/TX reverses Mn-induced glutamate transporter inhibition by enhancing activity, expression and trafficking of the transporters, 2)whether E2/TX effects on glutamate transporters are ER-subtype dependent, 3) whether TGF- D and TGF-E1 mediate ER-dependent E2/TX-reversal of Mn-induced inhibition of glutamate transporters, 4) whether E2/TX treatment leads to neuroprotection against Mn-induced neurotoxicity in vivo by enhancing glutamate transporters. Our studies will provide novel insights into the mechanism(s) underlying the neuroprotective role of E2/TX in the model of Mnism and will offer potential insights into novel targets for treatment of a wide array of neurodegenerative disorders.