权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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（由申请人提供）：帕金森病 (PD) 是一种神经退行性疾病，仅 10-20% 的病例可归因于遗传。流行病学证据表明，帕金森病在农村地区更为常见，其患病率的增加与使用杀虫剂、除草剂和重金属（包括锰 (Mn)）有关。长期接触高浓度锰会导致锰中毒，锰中毒与帕金森病有多种共同特征，但锰引起神经毒性的机制尚未完全确定。 Mn 会降低谷氨酸转运蛋白 GLT-1 的表达，从而调节突触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yin yang 1 (YY1)在Mn对GLT-1的影响中起着关键作用。因此，描述锰诱导的 GLT-1 表达失调的精确机制对于增进我们对锰神经毒性的理解至关重要。此外，识别锰诱导的 GLT-1 功能障碍的分子靶点将具有广泛的适用性，因为大量的神经退行性疾病，如 PD、阿尔茨海默病和肌萎缩侧索硬化症都与继发于 GLT-1 功能障碍的谷氨酸稳态紊乱有关。因此，我们的长期目标是了解与兴奋性神经变性相关的 GLT-1 表达调节机制。我们的近期目标是确定 YY1 如何调节 Mn 诱导的 GLT-1 抑制。在这里，我们提供了初步数据，描述了 YY1 在 Mn 诱导的 GLT-1 抑制中的先前未知的作用。在我们的研究结果中，我们确定 Mn 通过 NF-κB 增加 YY1 表达。此外，表观遗传修饰剂组蛋白脱乙酰酶 (HDAC) 作为 YY1 的共阻遏物，而 HDAC 抑制剂 (HDACi) 可以逆转 Mn 诱导的 GLT-1 启动子活性抑制。鉴于这些观察结果，我们假设 Mn 诱导的 GLT-1 抑制是通过 NF-κB 依赖性 YY1 激活来抑制的，而 HDAC 则充当辅助抑制因子，介导了 Mn 诱导的神经毒性。我们提出的工作是该领域第一个在转录水平上探索 Mn 通过 YY1 对 GLT-1 表达的影响的工作。我们的假设将在以下具体目标中得到检验：1) 使用星形胶质细胞特异性 YY1 条件敲除小鼠确定星形胶质细胞 YY1 是否通过损害 GLT-1 表达和功能来介导 Mn 诱导的神经毒性，2) 使用原代星形胶质细胞在体外描述 Mn 诱导的 YY1 激活的分子机制及其在调节 GLT-1 功能中的作用，3) 测试 Mn 增强的 YY1 表达和随后的 GLT-1 抑制是否受到 HDAC 表观遗传修饰的调节。我们的研究将为 YY1 通路在 Mn 诱导的 GLT-1 功能抑制和 Mn 诱导的神经毒性中的作用机制提供新的见解。此外，这项研究的结果将为与 GLT-1 功能损伤和兴奋性毒性相关的神经退行性疾病提供新的治疗策略。