Characterization of the Fidelity to PD of a Unique Rat Model

独特大鼠模型的 PD 保真度表征

基本信息

批准号：
9129773
负责人：
D. Allan Butterfield
金额：
$ 18.81万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9129773
关键词：
ATP phosphohydrolase Age Age-Months Animal Model Anosmia Antioxidants Autophagocytosis Behavior Biochemical Biochemistry Biological Bradykinesia Brain Brain region Caenorhabditis elegans Characteristics Cognition Complex Corpus striatum structure Dependence Disease Dopamine Dopamine Agonists Elderly Environmental Risk Factor Etiology Exhibits Future Genes Genetic Genetic Models Glutathione Glutathione Disulfide Goals Health Heat shock proteins Heavy Metals Herbicides Histopathology Human Image Impaired cognition Investigation Knock-out Knowledge LRRK2 gene Lead Levodopa Lewy Bodies Link Lipid Peroxidation Metabolic Mitochondria Modeling Molecular Monoamine Oxidase B Movement Mus Mutation Nature Nerve Degeneration Neurobehavioral Manifestations Neurodegenerative Disorders Oxidation-Reduction Oxidative Stress PINK1 gene PTEN-induced putative kinase Parkinson Disease Pathogenesis Pathology Pathway interactions Patients Pharmacological Treatment Physiology Process Proteins Proteomics Publishing Rattus Research Research Personnel Rest Tremor Rodent Model Role Signs and Symptoms Smell Perception Solvents Substantia nigra structure Susceptibility Gene Symptoms Techniques Testing age related alpha synuclein base brain size dopaminergic neuron drug discovery environmental stressor gene interaction inhibitor/antagonist innovation insight learned behavior mitochondrial dysfunction motor deficit mouse model neurochemistry neuron loss novel oxidation parkin gene/protein pre-clinical research premature response small molecule stress protein success tool

项目摘要

DESCRIPTION (provided by applicant): Parkinson disease (PD), the second most prevalent neurodegenerative disorder of the elderly, is associated with movement and cognitive symptoms, and current pharmacological treatments result in transient symptomatic relief but are not disease-modifying. PD results from degeneration of dopaminergic neurons in the substantia nigra (SNPC), and loss of striatal dopaminergic function is undoubtedly the cause of the symptoms of PD. Current treatments for PD have been focused on augmenting dopamine levels and include levodopa, dopamine agonists, and MAO-B inhibitors. Arguably the first biochemical deficits in PD, which arise before symptoms appear, are loss of parenchymal glutathione (GSH), the brain's major small molecule antioxidant, and elevation of its oxidized form (GSSG) (Chinta et al., 2006). This has led researchers to show that PD is associated with oxidative stress, though the cause of PD remains unknown. Familial PD cases have been linked to altered genes, among which is PTEN-induced putative kinase-1 (Pink-1). Genetic models of PD, mostly mice bearing mutations in PD-relevant genes, for unknown reasons do not have pathology or dopaminergic neuronal loss in the SNPC unlike PD patients. An ideal animal model of PD would display progressive loss of dopaminergic neurons, and formation of Lewy bodies, exhibit motor deficits, and also mimic non-dopaminergic characteristics of PD, i.e., loss of cognition and sense of smell (anosmia). It is thought that no mouse model of PD fulfills these criteria. Sage Labs (Horizon) has produced a Pink-1 knockout rat [PINK-1 KO] that exhibits progressive dopaminergic loss in the SNPC, moderate to severe motor deficits, and non-motor characteristics of PD, i.e., anosmia. At 8 months of age, abundant pathology in the SNPC and PD-relevant symptomology are present. This may be the only rodent model of PD that has PD-relevant pathology in the SNPC. It would be helpful to utilize this exciting novel biological tool or environmental studies relevant to environmental-gene interaction in the neurodegeneration associated with PD. However, this laudable goal is presently premature since this rat has not been fully characterized for goodness of fit to PD. Hence, to fill this critical need this R21 proposal will achieve the goal of characterizing this unique rat model of PD to test the overall hypothesis that this unique rat has high fidelity to PD in terms of pathology, biochemistry, and behavior. If this hypothesis is sustained by these studies, future investigations will employ this rat to probe gene-environmental interactions of relevance to PD.

描述（由申请人提供）：帕金森病（PD）是老年人中第二常见的神经退行性疾病，与运动和认知症状有关，目前的药物治疗可导致短暂的症状缓解，但不能缓解帕金森病的疾病。黑质（SNPC）多巴胺能神经元的变性和纹状体多巴胺能功能的丧失无疑是帕金森病症状的原因，目前对帕金森病的治疗主要集中在加重帕金森病的症状。多巴胺水平，包括左旋多巴、多巴胺激动剂和 MAO-B 抑制剂可以说，PD 中在症状出现之前出现的第一个生化缺陷是脑实质谷胱甘肽 (GSH)（大脑主要小分子抗氧化剂）的损失及其氧化水平的升高。 (GSSG)（Chinta 等，2006）这使得研究人员发现 PD 与氧化应激有关，尽管氧化应激是其病因。帕金森病的家族性病例与基因改变有关，其中包括 PTEN 诱导的推定激酶 1 (Pink-1)，帕金森病的遗传模型大多是携带帕金森病相关基因突变的小鼠，但原因不明。与 PD 患者不同，SNPC 中没有病理学或多巴胺能神经元损失，理想的 PD 动物模型将显示多巴胺能神经元进行性损失，并形成路易体，表现出运动缺陷，并且还模仿。 PD 的非多巴胺能特征，即认知和嗅觉丧失（嗅觉丧失），Sage Labs (Horizon) 已生产出 Pink-1 基因敲除大鼠 [PINK-1]。 KO] 表现出 SNPC 进行性多巴胺能丧失、中度至重度运动缺陷以及 PD 的非运动特征，即嗅觉丧失。存在 SNPC 中丰富的病理学和 PD 相关症状，这可能是唯一具有 SNPC 中 PD 相关病理学的 PD 啮齿动物模型，利用这种令人兴奋的新型生物学工具或与相关的环境研究将有所帮助。然而，这个值得称赞的目标目前还为时过早，因为尚未完全表征该大鼠与 PD 的拟合优度。因此，为了满足这一关键需求，该 R21 提案将实现表征的目标。这种独特的帕金森病大鼠模型是为了检验这种独特的大鼠在病理学、生物化学和行为方面对帕金森病具有高度保真度的总体假设。如果这些研究证实了这一假设，未来的研究将利用这种大鼠来探测基因环境。与 PD 相关的相互作用。