Mechanism of manganese-induced impairment of astrocytic glutamate transporters

锰引起星形胶质细胞谷氨酸转运蛋白损伤的机制

基本信息

批准号：
8964605
负责人：
Eun Sook Yu Lee
金额：
$ 32.92万
依托单位：
MEHARRY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-15 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8964605
关键词：
Acetylation Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Astrocytes Attenuated Binding Brain Cells Chronic Coculture Techniques Complement Factor B Consensus Cre-LoxP Data Disease Drug Targeting Environmental Risk Factor Epidemiologic Studies Epidemiology Epigenetic Process Exposure to Functional disorder Genes Genetic Genetic Predisposition to Disease Glial Fibrillary Acidic Protein Glutamate Transporter Glutamates Goals Heavy Metals Herbicides Histone Deacetylase Inhibitor Histones Homeostasis Impairment In Vitro Inflammation Knock-out Knockout Mice Manganese Mediating Mediator of activation protein Modeling Modification Molecular Molecular Profiling Molecular Target Mus Mutation Nature Nerve Degeneration Neurodegenerative Disorders Neuronal Injury Neurons Nuclear Outcome Study Oxidative Stress Parkinson Disease Pathway interactions Pesticides Phosphotransferases Play Prevalence Proteins Regulation Reporter Repression Risk Factors Role Secondary to Signal Transduction Site Synapses Technology Testing Therapeutic Toxic Environmental Substances Toxic effect Transgenic Organisms Up-Regulation Work Yin-Yang casein kinase II excitotoxicity in vivo inhibitor/antagonist insight mRNA Expression nervous system disorder neurotoxicity novel novel therapeutics overexpression prevent promoter protein expression public health relevance rural area transcription factor

项目摘要

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a neurodegenerative disease which can be ascribed in only 10-20% of cases to genetics. Epidemiological evidence suggests that PD is more common in rural areas, where its increased prevalence is associated with the use of pesticides, herbicides and heavy metals, including manganese (Mn). Chronic exposure to high Mn levels causes manganism, which has multiple shared features with PD, but the mechanisms by which Mn induces neurotoxicity have yet to be fully established. Mn decreases expression of glutamate transporter GLT-1, which regulates synaptic glutamate levels and prevents excitotoxic neuronal injury. Our preliminary studies indicate that the transcription factor yin yang 1 (YY1) plays a critical role in the effect of Mn on GLT-1. Accordingly, delineating the precise mechanism of Mn-induced dysregulation of GLT-1 expression is critical in advancing our understanding of Mn neurotoxicity. Moreover, identifying molecular targets of Mn-induced GLT-1 dysfunction will have broad applicability, since a plethora of neurodegenerative diseases, such as PD, Alzheimer's disease and amyotrophic lateral sclerosis are associated with perturbed glutamate homeostasis secondary to GLT-1 dysfunction. Thus, our long-term goal is to understand the mechanisms involved in the regulation of GLT-1 expression in relation to the excitotoxic neurodegeneration. Our immediate objective is to determine how YY1 regulates Mn-induced repression of GLT-1. Here, we present preliminary data characterizing a previously unknown role of YY1 in Mn-induced repression of GLT-1. Among our findings, we determined that Mn increases YY1 expression via NF-κB. In addition, epigenetic modifier histone deacetylases (HDACs) serve as co-repressors of YY1, and HDAC inhibitors (HDACi) reverse Mn-induced repression of GLT-1 promoter activity. Given these observations, we hypothesize that Mn-induced GLT-1 repression by NF-κB-dependent YY1 activation, with HDACs acting as co-repressors, mediates Mn-induced neurotoxicity. Our proposed work is the first in the field to explore the effect of Mn on GLT-1 expression via YY1 at the transcriptional level. Our hypothesis will be tested in the following specific aims: 1) Determine if astrocytic YY1 mediates Mn-induced neurotoxicity by impairing GLT-1 expression and function using astrocyte-specific YY1 conditional knockout mice, 2) Delineate the molecular mechanisms of Mn-induced activation of YY1 and its role in regulating GLT-1 function in vitro using primary astrocytes, and 3) Test if Mn- enhanced YY1 expression and the ensuing GLT-1 repression are regulated by HDAC epigenetic modification. Our studies will provide novel insights into the mechanism(s) underlying the role of the YY1 pathway in Mn-induced repression of GLT-1 function and Mn-induced neurotoxicity. Moreover, the outcome of this study will offer novel therapeutic strategies for neurodegenerative diseases associated with impairment in GLT-1 function and excitotoxicity.

描述（由适用提供）：帕金森氏病（PD）是一种神经退行性疾病，只能在10-20％的病例中归因于遗传学。流行病学证据表明，PD在农村地区更为普遍，在农村地区，其患病率与使用农药，除草剂和重金属有关，包括锰（MN）。长期暴露于高Mn水平会导致锰，具有与PD的多个共享特征，但是MN诱导的神经毒性的机制尚未完全确定。 MN降低了谷氨酸转运蛋白GLT-1的表达，该转运蛋白GLT-1调节合成谷氨酸水平并防止兴奋性神经元损伤。我们的初步研究表明，转录因子阴1（yy1）在MN对GLT-1的影响中起关键作用。根据以下内容，描述MN诱导的GLT-1表达失调的确切机制对于促进我们对MN神经毒性的理解至关重要。此外，由于多种神经退行性疾病，例如PD，Alzheimer病和肌萎缩性的侧面硬化症，鉴定MN诱导的GLT-1功能障碍的分子靶标将具有广泛的适用性。这就是我们的长期目标是了解与兴奋性神经变性有关的GLT-1表达调节中的机制。我们的直接目标是确定YY1如何调节Mn诱导的GLT-1表达。在这里，我们介绍了YY1在Mn诱导的GLT-1表达中的先前未知作用的初步数据。在我们的发现中，我们确定MN通过NF-κB增加了YY1的表达。此外，表观遗传修饰剂组蛋白脱乙酰基酶（HDACS）用作YY1的共抑制剂，HDAC抑制剂（HDACI）反向MN诱导的GLT-1启动子活性的表达。鉴于这些观察结果，我们假设MN诱导的GLT-1通过NF-κB依赖性YY1激活，HDAC用作共阻剂，介导MN诱导的神经毒性。我们提出的工作是该领域的第一个在转录级别通过YY1探索MN对GLT-1表达的影响的工作。我们的假设将在以下特定目的中进行检验：1）确定星形胶质细胞YY1通过使用星形胶质细胞特异性YY1的有条件敲除小鼠来介导MN诱导的神经毒性，并通过损害GLT-1的表达和功能，2）DELINEATE，DELINEADE使用MN诱导的YY1的分子机制，并使用MN诱导的YY1的作用，并在YY1的primation rtt strountion Indignation Indignation Indectry strigation Indectros rtt strip strip nocion int strigation in yy1。测试是否通过HDAC表观遗传学修饰调节Mn增强的YY1表达和确保GLT-1抑制作用。我们的研究将提供有关YY1途径在MN诱导的GLT-1功能表达和MN诱导的神经毒性中的作用的机制的新见解。此外，这项研究的结果将为与GLT-1功能和兴奋性障碍相关的神经退行性疾病提供新的治疗策略。