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（申请人证明）：帕金森氏病（PD）是AA流行病学证据表明，PD I在农村地区更为普遍，在农村地区，其使用率增加与农药，除草剂和重金属相关。 MN）。损伤表明，转录因子Yin Yang 1（YY1）在MN对GLT-1的影响中起着关键作用。了解MN诱导的GLT-1功能障碍的MN神经毒性。。在MN诱导的GLT-1中，我们确定MN通过NF-κB增加了YY1的表达。 Mn IID抑制GLT-1启动子活性。转录水平的YY1。 - YY1及其在使用原发性星形胶质细胞在体外调节GLT-1功能中的作用，并通过HDAC表观遗传学修饰来调节Andhanced表达和随之而来的GLT-1抑制作用。此外，MN诱导的GLT-1功能和MNDECITY的YY1途径。