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：
8269823
负责人：
Eun Sook Yu Lee
金额：
$ 29.01万
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/8269823
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 Corpus striatum structure 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 ICI 182780 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 National Institute of Environmental Health Sciences National Institute of Neurological Disorders and Stroke Nerve Degeneration Neurobiology Neurodegenerative Disorders Neurons Neuroprotective Agents Neurosciences Neurosciences Research Nuclear Nuclear Protein 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 receptor restoration role model skills success symposium trafficking translational neuroscience uptake

项目摘要

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.

我们研究的长期目标是阐明17B-雌二醇（E2）和选择性雌激素受体调节剂（SERM）的神经保护机制，并制定策略以发现合适的SERM，这些SERM可以用作神经保护剂，而这些神经保护剂无需女性或对男性女性的癌症风险而没有癌症的风险。 17b-雌二醇（E2）已显示在各种神经退行性疾病中具有神经保护作用，例如阿尔茨海默氏病（AD）和帕金森氏病（PD）。在AD，PD和缺血的实验模型中，一些包括他莫昔芬（TX）在内的Serms也具有神经保护特性。尽管涉及神经退行性的机制尚未完全理解，但已知星形胶质细胞谷氨酸转运蛋白的损害在各种神经退行性疾病的发病机理中起关键作用，包括AD和PD以及由长期暴露于Manganese（MN）引起的锰（MNISM）。 MN抑制谷氨酸摄取并降低谷氨酸转运蛋白的表达，这对于调节细胞外谷氨酸水平至关重要。尽管E2似乎调节星形胶质酸谷氨酸转运蛋白的表达，但E2调节的机制仍然难以捉摸。此外，由于缺乏或对乳房和子宫的负面影响，TX和其他SERM被认为在E2上被认为具有治疗性有利的，不幸的是，尚未检查以确定它们是否具有潜在的有益的星形胶质体谷氨酸转运蛋白表达或活性，在需要解决领域的赤字。为了解决我们在这一重要领域的知识中的这些差距，我们将使用锰（MNism）作为谷氨酸转运蛋白诱导的神经变性的实验模型，因为MN治疗已很好地确定以诱导与神经毒性相关的谷氨酸转运蛋白的损害。我们的中心假设是，E2和TX可以通过调节转运蛋白运输和雌激素受体（ER）依赖性转运蛋白通过调节生长因子的调节，尤其是转化生长因子（TGF）-A和TGF-B1来逆转MN诱导的抑制谷氨酸转运蛋白活性。 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诱导的谷氨酸转运蛋白抑制作用，4）E2/TX治疗是否通过增强谷氨酸转运蛋白来对Mn诱导的MN诱导的神经毒性产生神经保护作用。我们的研究将提供对E2/TX在MNISM模型中神经保护作用的基础机制的新见解，并将为治疗多种神经退行性疾病的新型靶标提供潜在的见解。