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：
8478220
负责人：
ASGAR ZAHEER
金额：
$ 31.88万
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/8478220
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.

描述（由申请人提供）：帕金森病是一种进行性致残且致命的疾病。据估计，每年诊断出 60,000 个新病例，加入目前患有帕金森病的 100 万美国人的行列，而且这种疾病无法治愈。 PD 的特征是大脑中存在退化的多巴胺能神经元、路易体和活化的神经胶质细胞。虽然帕金森病的病因尚不清楚，但已知接触环境神经毒性污染物 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 与人类和动物帕金森病的病理学有关PD 模型。总是，活化的神经胶质细胞不仅存在，而且持续存在于帕金森病的大脑中，这可以通过分泌有害的细胞因子和趋化因子来促进帕金森病的维持和进展。我们实验室发现并表征的神经胶质成熟因子 (GMF) 是哺乳动物大脑/中枢神经系统中的保守蛋白。我们已经证明了 GMF 在各种因素和刺激激活星形胶质细胞和小胶质细胞并导致神经元细胞死亡中的重要作用。我们假设 GMF 也参与 PD 的发病机制。这一新的假设是基于 GMF 已证实的功能以及我们最近的免疫组织学检查，该检查揭示了死后 PD 大脑的黑质纹状体区域以及 PD 实验动物模型的大脑中存在大量活化的星形胶质细胞、小胶质细胞和 GMF 的突出性其中 GMF、星形胶质细胞和小胶质细胞的变化先于多巴胺神经元的损失。我们提出了三个具体目标来支持我们的假设。具体目标 1 将检查 GMF 与 PD 病理学之间的关联。我们还将检查 GMF 依赖性神经胶质细胞激活是否是产生促炎介质所必需的，而促炎介质负责多巴胺能神经元的变性。具体目标 2 将绘制含有 GMF 的野生型和 GMF 缺陷型 (GMF-KO) 小鼠中 MPTP 诱导的多巴胺能神经元损失的比较发病机制和进展。我们将比较 Wt 小鼠和 GMF-KO 小鼠的组织病理学特征、神经化学变化和行为运动缺陷。具体目标 3 将评估我们用 GMF 特异性 siRNA 靶向 GMF 的新治疗方法对神经炎症/神经退行性疾病的抑制作用以及治疗效果，以沉默 MPTP 中毒小鼠中的 GMF 信号传导。