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Estrogen-neuroprotection due to astroglial Glu transporters occurs via TGF-a/b1

星形胶质细胞 Glu 转运蛋白通过 TGF-a/b1 发挥雌激素神经保护作用

基本信息

批准号：
7762128
负责人：
Eun Sook Yu Lee
金额：
$ 27.85万
依托单位：
MEHARRY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-11 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7762128
关键词：
Academic Medical Centers Address Adverse effects African American Agonist Alzheimer&apos s Disease Applications Grants Area Astrocytes Attenuated Automobile Driving Biological Models Biomedical Research Biotinylation Book Chapters Books Brain Breast Cell Surface Proteins Cell membrane Cell surface Chronic Collaborations Collection Communities Confocal Microscopy Consult Core Facility Corpus striatum structure Credentialing Data Data Analyses Dependency Development Doctor of Philosophy Educational process of instructing Estradiol Estrogen Receptors Estrogens Excitatory Amino Acid Transporter 1 Exhibits Experimental Designs Experimental Models Exposure to Faculty Female Fostering Funding Future GLAST Protein Glial Fibrillary Acidic Protein Glutamate Transporter Glutamates Goals Grant Growth Factor Health Human Image Imaging Techniques Immunohistochemistry Impairment Implant In Vitro Individual Injection of therapeutic agent Institution Ischemia Journals Knowledge Laboratories Lead Learning Letters Manganese Mediating Mediator of activation protein Medical Students Mentors Methodology Minority Modeling Morphology Nerve Degeneration Neurobiology Neurodegenerative Disorders Neurons Neuroprotective Agents Neurosciences Neurosciences Research Nuclear Nuclear Protein Nuclear Proteins Oxidative Stress Paper Parkinson Disease Pathogenesis Pathway interactions Peer Review Play Prevention Procedures Productivity Property Proteins Publications Publishing Rattus Regulation Research Research Personnel Role Science Scientist Selective Estrogen Receptor Modulators Signal Transduction Societies Students Tamoxifen Techniques Testing Time Training Transforming Growth Factors Uterus Visit Western Blotting Woman Work Writing cancer risk career career development experience extracellular falls fluoro jade graduate student in vivo insight interest journal article mRNA Expression medical schools meetings member men neuroprotection neurotoxicity neurotoxicology novel prevent professor programs protein expression public health relevance receptor restoration role model skills success symposium trafficking translational neuroscience uptake

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of our research is to elucidate the neuroprotective mechanisms of 17b-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. 17b- 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)-a and TGF-b1. 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- a and TGF-b1 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. PUBLIC HEALTH RELEVANCE: Impairment of astroglial glutamate transporters is associated with various neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD) and manganism, which is caused by chronic manganese (Mn) exposure. Since tamoxifen (TX) and 172-estradiol (E2) have been shown to be neuroprotective in various neurodegenerative diseases, in this proposal, we will test whether E2/SERMs can exert neuroprotective effects by attenuating Mn-induced impairment of astroglial glutamate transporters. Moreover, we will also test whether growth factors, TGF-1/2, mediate E2/TX-induced restoration of glutamate transporters.

描述（由申请人提供）：我们研究的长期目标是阐明17 b-雌二醇（E2）和选择性雌激素受体调节剂（SERM）的神经保护机制，并开发发现合适的SERM的策略，这些SERM可用作神经保护剂，而不会对女性产生癌症风险或对男性产生女性化效应。17 b-雌二醇（E2）已被证明在各种神经退行性疾病如阿尔茨海默病（AD）和帕金森病（PD）中具有神经保护作用。包括他莫昔芬（TX）在内的一些SERM在AD、PD和缺血的实验模型中也具有神经保护特性。虽然参与神经退行性变的机制还不完全清楚，但已知星形胶质细胞谷氨酸转运体的损伤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以及由慢性暴露于锰（Mn）引起的锰中毒（Mnism）。Mn抑制谷氨酸摄取并降低谷氨酸转运蛋白表达，这在调节细胞外谷氨酸水平中至关重要。虽然E2似乎调节星形胶质细胞谷氨酸转运蛋白的表达，E2调节的机制仍然难以捉摸。此外，TX和其他SERM由于其对乳房和子宫的负面副作用缺乏或减少而被认为在治疗上潜在地优于E2，不幸的是，尚未进行检查以确定它们是否发挥星形胶质细胞谷氨酸转运蛋白表达或活性的潜在有益增强，这是该领域需要解决的缺陷。为了解决我们在这一重要领域的知识差距，我们将使用锰中毒（Mnism）作为受损谷氨酸转运蛋白诱导的神经退行性变的实验模型，因为锰治疗已被公认为诱导与神经毒性相关的谷氨酸转运蛋白受损。我们的中心假设是，E2和TX可以逆转锰诱导的谷氨酸转运蛋白活性的抑制，通过调节转运蛋白的运输和通过调节生长因子，特别是转化生长因子（TGF）-α和TGF-β 1的谷氨酸转运蛋白的雌激素受体（ER）依赖性表达。我们的总体假设将在以下具体目标中得到检验：1）E2/TX是否通过增强转运体的活性、表达和运输来逆转Mn诱导的谷氨酸转运体抑制，2）E2/TX对谷氨酸转运体的作用是否是ER亚型依赖性的，3）TGF-α和TGF-β 1是否介导Mn诱导的谷氨酸转运体抑制的ER依赖性E2/TX逆转，4）E2/TX处理是否通过增强谷氨酸转运体而导致针对Mn诱导的体内神经毒性的神经保护。我们的研究将为Mnism模型中E2/TX的神经保护作用机制提供新的见解，并将为治疗各种神经退行性疾病的新靶点提供潜在的见解。公共卫生相关性：星形胶质细胞谷氨酸转运体的损伤与多种神经退行性疾病相关，包括阿尔茨海默病（AD）、帕金森病（PD）和锰中毒，锰中毒是由慢性锰（Mn）暴露引起的。由于他莫昔芬（TX）和172-雌二醇（E2）已被证明是在各种神经退行性疾病的神经保护，在这个建议中，我们将测试是否E2/SERM可以发挥神经保护作用，通过减弱锰诱导的损害星形胶质细胞谷氨酸转运蛋白。此外，我们还将测试生长因子TGF-1/2是否介导E2/TX诱导的谷氨酸转运体的恢复。