Glia maturation factor dependent mast cell activation in Parkinson's disease

帕金森病中神经胶质成熟因子依赖性肥大细胞激活

• 批准号: 8815697
• 负责人: ASGAR ZAHEER
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8815697
• 关键词: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 1-Methyl-4-phenylpyridinium; Acute; Adenoviruses; Affect; Allergic Reaction; Alzheimer' s Disease; American; Animal Model; Antioxidants; Behavioral; Bone Marrow; Bradykinesia; Brain; Cell Communication; Cell secretion; Cells; Cessation of life; Chronic; Clinical; Coculture Techniques; Development; Direct Costs; Disease; Etiology; Exposure to; Facilities and Administrative Costs; Free Radicals; Functional disorder; Glia Maturation Factor; Glutathione Reductase; Goals; Health; Healthcare; Human; Human Pathology; In Vitro; Infiltration; Inflammatory; Inflammatory Response; Ions; Iowa; Janus kinase; Laboratories; Lewy Bodies; Life; Lipid Peroxidation; MAP Kinase Gene; MAPK14 gene; Measures; Mediating; Mediator of activation protein; Movement Disorders; Mus; Natural Immunity; Nerve Degeneration; Nerve Fibers; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neurons; Operative Surgical Procedures; Oxidative Stress; Oxides; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Phase; Proteins; Reduced Glutathione; Research; Rest Tremor; Role; STAT protein; Signal Pathway; Symptoms; T-Lymphocyte; Testing; Therapeutic Agents; Therapeutic Intervention; Thiobarbituric Acid Reactive Substances; Time; Toxic effect; Toxin; Umbilical Cord Blood; United States; Universities; Veterans; Wild Type Mouse; acquired immunity; base; brain cell; chemokine; combat; cytokine; design; dopaminergic neuron; effective therapy; glutathione peroxidase; in vivo; mast cell; mouse model; neurochemistry; neuroinflammation; neurotoxic; novel; novel therapeutics; pollutant; public health relevance; reconstitution; research study

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a chronic and progressive movement disorder characterized by the degeneration of dopaminergic neurons and presence of Lewy body. Clinically, PD is characterized by resting tremor, rigidity, bradykinesia and postural instability. Inflammatory responses manifested by glia, T cell infiltration, and increased expression of inflammatory toxic mediators in the glial and neuronal cells, are prominent features of PD. Neuroinflammation is an important contributor to the pathogenesis of PD and may further augment progressive loss of nigral dopaminergic neurons. Approximately one million Americans are living with PD. At present, the annual combined direct and indirect cost of healthcare for PD patients is estimated to be nearly $25 billion in the USA. However, the etiology of PD remains unknown; and though there is currently no cure, but there are treatment options available such as medication and surgery to manage its symptoms. The lack of treatments for the progressive phase of PD represents a significant gap in the clinician's ability to treat this disease. The goal of this proposal is to study the role of glia maturation factor (GMF), a novel protein first discovered in our laboratory at the University of Iowa, in the activation of mast cells and secretion of proinflammatory mediators that are responsible for neurodegeneration in the pathogenesis of PD. Emerging evidence suggests glia-neuron-mast cell communications in neuroinflammatory conditions. We hypothesize that GMF-dependent activation of mast cell is associated with the pathophysiology of PD. We will elucidate the regulatory role of GMF in degeneration of neurons in order to provide a mechanistic basis for GMF-mediated pathogenesis in the 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) mouse model of PD. We will examine whether GMF is required in human and mouse primary mast cell activation and secretion of proinflammatory cytokines/chemokines and free radical that are responsible for degeneration of dopaminergic neurons following parkinsonian toxin 1-methyl-4- phenyl-pyridinium ion (MPP+) treatment in in vitro studies. We will analyze the mechanistic pathways involved in the activation of mast cells by GMF. Next, we will investigate if GMF exerts its effects by modulating mast cells in degeneration of nigrostriatal dopaminergic neurons in mouse models of PD. For this purpose we will use both MPTP-induced acute and chronic mouse models. We will reconstitute mast cell deficient (W/Wv) mice with bone marrow-derived mast cells from GMF-deficient (GMFKO) mice or Wild type mice and challenge with MPTP. We will analyze MPTP-induced neuroinflammation, neurochemical deficits, nigrostriatal degeneration, and correlate with behavioral parameters in these animal models. The present study has significant clinical implications, and provides an efficient in vivo approach to test GMF- suppression strategies as therapeutic agents for neurodegenerative diseases, including PD.

描述（由申请人提供）： 帕金森病（Parkinson's disease，PD）是一种以多巴胺能神经元变性和路易体（Lewy body）存在为特征的慢性进行性运动障碍。临床上，PD以静止性震颤、僵硬、运动迟缓和姿势不稳定为特征。炎症反应表现为神经胶质细胞、T细胞浸润以及神经胶质细胞和神经元细胞中炎性毒性介质表达增加，是PD的突出特征。神经炎症是PD发病机制的重要贡献者，并可能进一步增加黑质多巴胺能神经元的进行性丢失。大约有一百万美国人患有PD。目前，在美国，PD患者每年的直接和间接医疗费用估计接近250亿美元。然而，PD的病因仍然未知;虽然目前没有治愈方法，但有可用的治疗方案，如药物和手术来控制其症状。PD进展期治疗的缺乏代表了临床医生治疗这种疾病的能力的显著差距。该提案的目的是研究胶质成熟因子（GMF）的作用，GMF是我们爱荷华州大学实验室首次发现的一种新蛋白，在肥大细胞活化和促炎介质分泌中起作用，这些介质是PD发病机制中神经变性的原因。新出现的证据表明神经炎症条件下的胶质-神经元-肥大细胞通讯。我们推测GMF依赖性肥大细胞活化与PD的病理生理学有关。我们将阐明GMF在神经元变性中的调节作用，以便为1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）小鼠PD模型中GMF介导的发病机制提供机制基础。我们将研究是否需要GMF在人类和小鼠的原代肥大细胞活化和分泌的促炎细胞因子/趋化因子和自由基，负责多巴胺能神经元变性后帕金森毒素1-甲基-4-苯基-吡啶离子（MPP+）治疗在体外研究中。我们将分析转基因食品激活肥大细胞的机制途径。接下来，我们将研究是否GMF发挥其作用，通过调节肥大细胞在黑质纹状体多巴胺能神经元的变性在小鼠模型的PD。为此，我们将使用MPTP诱导的急性和慢性小鼠模型。我们将用来自GMF缺陷（GMFKO）小鼠或野生型小鼠的骨髓来源的肥大细胞重建肥大细胞缺陷（W/Wv）小鼠，并用MPTP攻击。我们将分析MPTP诱导的神经炎症，神经化学缺陷，黑质纹状体变性，并与这些动物模型的行为参数。本研究具有重要的临床意义，并提供了一种有效的体内方法来测试GMF抑制策略作为神经退行性疾病（包括PD）的治疗剂。