GMF-dependent neuroinflammation and neurodegeneration

GMF 依赖性神经炎症和神经变性

• 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
• 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

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（申请人提供）：帕金森病是一种进行性致残和致命的疾病。据估计，每年有6万新病例被诊断出来，加入了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以脑内多巴胺能神经元变性、路易小体和活化的胶质细胞为特征。虽然PD的病因尚不清楚，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动物模型的病理有关。激活的神经胶质细胞不仅存在于PD脑中，而且持续存在，通过分泌有害的细胞因子和趋化因子促进PD的维持和进展。神经胶质成熟因子（glia maturity factor， GMF）是在哺乳动物脑/中枢神经系统中发现并鉴定的一种保守蛋白。我们已经证明了GMF在星形胶质细胞和小胶质细胞被各种因素和刺激激活导致神经元细胞死亡中的突出作用。我们推测GMF也参与PD的发病机制。这一新的假设是基于GMF的功能和我们最近的免疫组织学检查，这些检查显示死后PD大脑的黑质纹状体区域有大量激活的星形胶质细胞、小胶质细胞和GMF的突出，以及PD实验动物模型的大脑中GMF、星形胶质细胞和小胶质细胞的变化在多巴胺神经元丢失之前。我们提出了三个具体目标来支持我们的假设。特异性目的1将检查GMF和PD病理之间的关系。我们还将研究gmf依赖的胶质细胞激活是否需要产生导致多巴胺能神经元变性的促炎介质。特异性目标2将比较mptp诱导的含gmf野生型和gmf缺乏（GMF-KO）小鼠多巴胺能神经元损失的发病机制和进展。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。特异性目的3将评估我们的新治疗方法，即用GMF特异性siRNA靶向GMF，沉默mptp中毒小鼠的GMF信号，对神经炎症/神经变性的抑制和治疗效果。