Parkinsonian mouse model: impaired respiratory enzymes

描述（由申请人提供）：帕金森病（PD）的主要症状主要由黑质（SN）中多巴胺能（DA）神经元的死亡引起1，2。目前的干预措施改善了症状，但没有治疗方法来停止或延迟DA神经元的损失。一些研究结果表明，呼吸链功能障碍直接参与PD1.2的发病机制。然而，支持性数据是相关的或基于可能具有多效性效应的神经毒素和药物治疗。在这个提议中，我们将尝试在小鼠中验证一种新的独特的PD模型。如果成功的话，对该模型的研究可以直接验证DA神经元中的呼吸链功能障碍可以诱导PD的主要特征的假设。该模型还可以检验以下假设：生物能衰竭将增加活性氧（ROS）的形成，这将有助于呼吸链缺陷的DA神经元的退化。 具体目标是： 1.建立多巴胺能神经元氧化磷酸化破坏的组织特异性基因敲除小鼠。 2.确定DA神经元中的呼吸链功能障碍是否会诱导PD样表型，并验证这种方法作为帕金森病的新的独特模型。

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.