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

基本信息

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
项目类别：
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&apos 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

项目摘要

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（PD）是一种慢性进行性运动障碍，其特征是多巴胺能神经元变性和路易体的存在。临床上，PD的特征是静止性震颤、强直、运动迟缓和姿势不稳。以神经胶质细胞、T 细胞浸润以及神经胶质细胞和神经元细胞中炎症毒性介质表达增加为表现的炎症反应是 PD 的显着特征。神经炎症是帕金森病发病机制的一个重要因素，并可能进一步加剧黑质多巴胺能神经元的进行性丧失。大约有一百万美国人患有帕金森病。目前，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 的病因仍不清楚；尽管目前尚无治愈方法，但有一些治疗选择，例如药物和手术来控制其症状。 PD 进展期缺乏治疗方法表明临床医生治疗这种疾病的能力存在显着差距。该提案的目标是研究神经胶质成熟因子（GMF）的作用，这是我们在爱荷华大学实验室首次发现的一种新型蛋白质，在肥大细胞的激活和促炎介质的分泌中的作用，这些介质负责神经退行性变。 PD的发病机制。新的证据表明神经炎症条件下胶质细胞-神经元-肥大细胞之间存在通讯。我们假设肥大细胞的 GMF 依赖性激活与 PD 的病理生理学相关。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。我们将检查人类和小鼠原代肥大细胞的激活和促炎细胞因子/趋化因子和自由基的分泌是否需要 GMF，这些细胞因子是帕金森毒素 1-甲基-4-苯基吡啶鎓离子 (MPP+) 治疗后多巴胺能神经元变性的原因在体外研究中。我们将分析 GMF 激活肥大细胞的机制途径。接下来，我们将研究 GMF 是否通过调节肥大细胞在 PD 小鼠模型中黑质纹状体多巴胺能神经元变性中发挥作用。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，并与这些动物模型中的行为参数相关联。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。