GMF-dependent neuroinflammation and neurodegeneration

GMF 依赖性神经炎症和神经变性

基本信息

批准号：
8244904
负责人：
ASGAR ZAHEER
金额：
$ 33.03万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8244904
关键词：
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine 1-Methyl-4-phenylpyridinium Adenoviruses Affect Age American Animal Model Astrocytes Autopsy Behavioral Brain Cultured Cells Development Diagnosis Disease Experimental Animal Model Exposure to Gender Glia Maturation Factor Goals Human Human Pathology In Vitro Inflammation Inflammation Mediators Investigation Knock-out Knockout Mice Laboratories Lentivirus Vector Lewy Bodies Maintenance Mediator of activation protein Messenger RNA Microglia Molecular Profiling Mus Nerve Degeneration Neuraxis Neurodegenerative Disorders Neuroglia Neurons Normal tissue morphology Parkinson Disease Pathogenesis Pathology Production Proteins Reactive Nitrogen Species Reactive Oxygen Species Research Resistance Role Side Signal Transduction Small Interfering RNA Stimulus Techniques Testing Therapeutic Intervention Time Transfection Treatment Efficacy Wild Type Mouse base brain cell brain tissue chemokine comparative cytokine disorder control dopaminergic neuron effective therapy fetal motor deficit mouse model nervous system disorder neurochemistry neuroinflammation neuron loss neurotoxic novel novel therapeutic intervention overexpression pollutant prevent research study small hairpin RNA

项目摘要

DESCRIPTION (provided by applicant): Parkinson's disease is progressive disabling and fatal. It is estimated that 60,000 new cases are diagnosed each year, joining the 1 million Americans who currently have Parkinson's disease, and there is no cure for this disease. PD is characterized by the presence of degenerating dopaminergic neurons, Lewy bodies and activated glia in brain. Although, the cause of PD is not clear, exposure to environmental neurotoxic pollutant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is known to be associated with the pathology of human PD and in animal models of PD. Invariably, activated glia are not only present but are also persistent in PD brains which could facilitate maintenance and progression of PD by secreting deleterious cytokines and chemokines. The glia maturation factor (GMF), discovered and characterized in our laboratory, is a conserved protein in mammalian brain/central nervous system. We already demonstrated the prominent role of GMF in activation of astrocytes and microglia by various factors and stimuli leading to death of neuronal cells. We hypothesize that GMF is also involved in pathogenesis of PD. This novel hypothesis is based on the demonstrated functions of GMF and our recent immuno-histological examinations that revealed numerous activated astrocytes, microglia and the prominence of GMF in nigrostriatal region of postmortem PD brains, as well as, in brains of experimental animal model of PD in which the changes in GMF, astrocytes and microglia preceded the loss of dopamine neurons. We forward three specific aims to support our hypothesis. Specific Aim 1 will examine the association between GMF and the pathology of PD. We will also examine whether GMF-dependent glial activation is required in the production of proinflammatory mediators that are responsible for degeneration of dopaminergic neurons. Specific Aim 2 will chart the comparative pathogenesis and progression of MPTP-induced dopaminergic neuronal loss in GMF-containing wild type and in GMF-deficient (GMF-KO) mice. We will compare the histopathological features, neurochemical changes, and behavioral motor deficits in Wt mice with GMF-KO mice. Specific Aim 3 will evaluate the suppression of neuroinflammation/neurodegeneration and therapeutic efficacy of our novel therapeutic approach of targeting GMF with GMF-specific siRNA to silence the GMF-signaling in MPTP-intoxicated mice. PUBLIC HEALTH RELEVANCE: Parkinson's disease is one of the most prevalent and progressive neurological diseases that affects both genders and over 1 million Americans suffer from PD; approximately 40% of the victims are under the age of 60, and the lack of effective treatments for PD represents a significant gap in the ability to treat this devastating disease. Based on glia maturation factor's (GMF) ability to induce several well-established pro-inflammatory mediators, we hypothesize that GMF is involved in the pathogenesis of PD. The aim of this proposal is to elucidate GMF as a novel candidate for therapeutic intervention in PD; therefore, these studies may provide the scientific rationale for the development of a novel non-toxic therapy for PD.

描述（由申请人提供）：帕金森氏病是进行性残疾和致命的。据估计，每年诊断出60,000例新病例，加入目前患有帕金森氏病的100万美国人，并且无法治愈这种疾病。 PD的特征是存在退化多巴胺能神经元，Lewy身体和脑中活化的神经胶质。虽然，PD的原因尚不清楚，但已知暴露于环境神经毒性污染物1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）与人类PD和PD动物模型中的病理相关。始终存在活化的神经胶质，不仅存在，而且在PD大脑中也持续存在，可以通过分泌有害的细胞因子和趋化因子来促进PD的维持和进展。在我们的实验室中发现和表征的神经胶质成熟因子（GMF）是哺乳动物脑/中枢神经系统中保守的蛋白质。我们已经证明了GMF通过各种因素和刺激导致神经元细胞死亡的各种因素和刺激在激活星形胶质细胞和小胶质细胞中的重要作用。我们假设GMF也参与了PD的发病机理。 This novel hypothesis is based on the demonstrated functions of GMF and our recent immuno-histological examinations that revealed numerous activated astrocytes, microglia and the prominence of GMF in nigrostriatal region of postmortem PD brains, as well as, in brains of experimental animal model of PD in which the changes in GMF, astrocytes and microglia preceded the loss of dopamine神经元。我们将三个特定的目标转发以支持我们的假设。具体目标1将检查GMF与PD病理之间的关联。我们还将研究在产生负责多巴胺能神经元退化的促炎介质的产生中是否需要使用GMF依赖性神经胶质激活。具体目标2将绘制含GMF的野生型和GMF缺乏型（GMF-KO）小鼠中MPTP诱导的多巴胺能神经元丧失的比较发病机理和进展。我们将使用GMF-KO小鼠比较WT小鼠中的组织病理学特征，神经化学变化和行为运动缺陷。具体目标3将评估我们使用GMF特异性siRNA靶向GMF的新型治疗方法对神经炎症/神经退行性的抑制和治疗功效，以使MPTP-Intoxicatic小鼠中的GMF信号沉默。公共卫生相关性：帕金森氏病是影响性别和超过100万美国人患有PD的最普遍和进步的神经系统疾病之一。大约40％的受害者年龄在60岁以下，缺乏有效的PD治疗方法是治疗这种毁灭性疾病的能力的显着差距。基于神经胶质成熟因子（GMF）诱导几种良好的促炎性介体的能力，我们假设GMF参与了PD的发病机理。该提案的目的是阐明GMF作为PD治疗干预的新型候选者；因此，这些研究可能为开发新的无毒治疗PD提供了科学原理。