The UCLA Udall Parkinson Disease Center of Excellence

新的证据表明，不同的突变导致家族性帕金森病（PD）的机制，也可能在散发性PD。这些新的数据表明细胞死亡前细胞功能障碍的重要性，以及非多巴胺能神经元参与疾病。因此，确定PD多种病因共同的细胞功能障碍机制可能会提供新的治疗靶点，以阻止或逆转疾病的进程。UCLA UDALL帕金森病卓越中心的这一更新申请侧重于功能障碍进展的研究，在表达PD致突变的互补模型中，以及在特征明确的患者人群中。该中心由5个项目组成，由行政核心和小鼠遗传学核心支持。在前三个项目中，我们建议继续协调当前奖项支持的多学科工作，以表征PD遗传小鼠模型中运动和非运动行为异常和神经病理学（项目1），神经递质释放异常（项目2）和突触功能异常（项目3）的进展，包括基于BAG技术的新型模型。这些项目将通过增加细胞模型（项目4）来补充，以分析导致小鼠中观察到的表型的细胞功能障碍的机制。研究功能障碍的进展也将是该中心新的面向患者的组成部分的重点。在这个项目（项目5）中，我们将进行诊断后疾病表型的临床纵向研究，包括精神和认知共病。与此同时，还将开发和验证一个经改进的与健康有关的生活质量评估工具。这些以患者为导向的研究将为将来分析来自同一患者的遗传物质提供关键的临床数据，并将我们的基础研究成果转化为改善的患者护理。 为了确定导致PD神经退行性变的细胞改变，UCLA UDALL帕金森病卓越中心将专注于运动症状及其进展发生之前发生的疾病的早期表现。结合实验模型和临床研究，我们中心的目标是了解这些细胞功能障碍的机制，以促进能够阻止疾病进程的治疗策略的发展。

New evidence indicates that distinct mutations cause familial Parkinson's disease (PD) by mechanisms that may also operate in sporadic PD. These new data point to the importance of cell dysfunction preceding cell death and to the involvement of non-dopaminergic neurons in the disease. Accordingly, identifying mechanisms of cellular dysfunction that are common to multiple causes of PD may offer new therapeutic targets to halt or reverse the course of the disease. This renewal application for the UCLA UDALL Parkinson Disease Center of Excellence focuses on studies of progression of dysfunction, in complementary models expressing PD-causing mutations, and in a well characterized patient population. The center consists of 5 projects supported by an administrative core and a mouse genetics core. In the first three projects we propose to continue coordinated multidisciplinary work supported by the current award to characterize the progression of motor and non-motor behavioral anomalies and neuropathology (project 1), anomalies of neurotransmitter release (project 2) and of synaptic function (project 3) in genetic mouse models of PD, including novel models based on BAG technology. These projects will be complemented by the addition of cellular models (project 4) to analyze the mechanisms of cellular dysfunction leading to the phenotypes observed in the mouse. Studying progression of dysfunction will also be the focus of the new patient oriented component of the Center. In this project (project 5), we will conduct clinical longitudinal studies of disease phenotype after diagnosis, including psychiatric and cognitive co-morbidities. This will be coupled to the development and validation of an improved health-related quality of life assessment tool. These patient oriented studies will provide crucial clinical data for future analyses of genetic material from the same patients and for the translation of our basic research efforts into improved patient care. To identify the cellular alterations leading to neurodegeneration in PD, the UCLA UDALL Parkinson Disease Center of Excellence will focus on early manifestations of the disease occurring before the onset of motor symptoms and their progression. Integrating experimental models and clinical studies, the goal of our center is to understand the mechanisms of these cellular dysfunctions in order to spur the development of therapeutic strategies able to stop the disease process.