Parkinsonian mouse model: impaired respiratory enzymes

帕金森病小鼠模型：呼吸酶受损

• 批准号: 6911384
• 负责人: LARS OLSON
• 金额: $ 14.99万
• 依托单位: KAROLINSKA INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-15 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6911384
• 关键词: Parkinson' s disease; apoptosis; behavior test; bioenergetics; cellular respiration; disease /disorder model; dopamine; electrophysiology; enzyme activity; free radical oxygen; genetically modified animals; immunocytochemistry; in situ hybridization; laboratory mouse; laser capture microdissection; mitochondrial DNA; mitochondrial disease /disorder; model design /development; neural degeneration; oxidative phosphorylation; respiratory enzyme; substantia nigra; terminal nick end labeling

DESCRIPTION (provided by applicant): Cardinal symptoms in Parkinson's disease (PD) result primarily from death of dopaminergic (DA) neurons in substantia nigra (SN)1,2. Current interventions ameliorate symptoms but there is no treatment to halt or delay loss of DA neurons. Several findings indicate that respiratory chain dysfunction is directly involved in the pathogenesis of PD1.2. However, the supporting data are either correlative or based on neurotoxin and drug treatments that may have pleiotropic effects. In this proposal, we will attempt to validate a new and unique model of PD in mice. If successful, studies on this model could directly test the hypothesis that respiratory chain dysfunction in DA neurons can induce cardinal features of PD. This model could also test the hypothesis that bioenergetic failure will increase the formation of reactive oxygen species (ROS), which will contribute to degeneration of respiratory chain deficient DA neurons. The specific aims are: 1. To generate tissue-specific knockout mice with disruption of oxidative phosphorylation in DA neurons. 2. To determine if respiratory chain dysfunction in DA neurons will induce a PD like phenotype and validate this approach as a new and unique model of Parkinson's Disease.

描述（由申请人提供）：帕金森病（PD）的主要症状主要由黑质（SN）1,2中的多巴胺能（DA）神经元死亡引起。目前的干预措施可以改善症状，但没有治疗方法可以阻止或延迟DA神经元的丧失。多项研究结果表明，呼吸链功能障碍直接参与了PD1.2的发病机制。然而，支持数据要么是相关的，要么是基于神经毒素和药物治疗，这些治疗可能具有多效性。在这项提议中，我们将尝试验证一种新的和独特的小鼠PD模型。如果成功，该模型的研究可以直接验证DA神经元呼吸链功能障碍可诱导PD主要特征的假设。该模型还可以验证生物能量衰竭会增加活性氧（ROS）的形成，从而导致呼吸链缺陷DA神经元变性的假设。