The UCLA UDALL Parkinson Disease Center of Excellence

加州大学洛杉矶分校 UDALL 帕金森病卓越中心

• 批准号: 7439089
• 负责人: MARIE-FRANCOISE S CHESSELET
• 金额: $ 193.59万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7439089
• 关键词: UCLA; UDALL; Parkinson; Disease; Center

DESCRIPTION (provided by applicant): 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. Project 1 Title: Progression of Behavioral and Pathologic Defects Preceding DA Cell Death in Mouse Models of PD PI: Marie-Francoise Chesselet, MD, PhD DESCRIPTION (provided by applicant): New evidence indicates that distinct mutations cause familial Parkinson's disease (PD) by mechanisms that may also operate in sporadic PD. During the current funding period we have identified cellular dysfunction without cell death in mice expressing various mutations known to cause PD in humans. In this renewal application we will test the hypothesis that common mechanisms of dysfunction may be induced by distinct mutations and offer therapeutic targets for treatment at early stages of the disease, before further cell death causes irreversible damage. Project 1. 2. and 3 form the continuation of the current award and will continue to use a multidisciplinary approach to uncover the mechanisms of neuronal dysfunction in existing and novel mouse models. In specific aim 1 of project 1 we will determine the progression of behavioral deficits and neuropathology in already available mice overexpressing alpha-synuclein under different promoters and parkin KO mice. We will use a battery of sensitive motor tests we have developed to assess the motor phenotype of the mice, and will extend this analysis to non-motor behaviors because related symptoms can have a major impact on patient quality of life, as examined in project 5 of the Center. We will use immunohistochemistry to determine the progression of alpha-synuclein pathology and glial activation throughout multiple brain regions known to be affected in PD, and to detect anomalies in the expression of proteins involved in neurotransmitter release and examined in project 4 of the Center. We will use ligand binding and molecular approaches to identify dysregulation of dopaminergic transmission that will be further examined with neurochemical approaches in project 2 and with electrophysiology in project 3. Finally, eventual cell loss in brain regions that are affected in PD (locus coeruleus, ventral medulla, nigrostriatal dopaminergic neurons) will be assessed in older animals with unbiased stereology. In specific aim 2, we will extend this analysis to novel mouse models generated in the Mouse Genetics Core with state of the art BAG technology. These include a mouse model expressing a parkin mutation shown to cause the loss of dopaminergic neurons in Drosophila. These mice will be characterized with the same methods described above, before being further analyzed in projects 2 and 3. Studies in project 1 will parallel longitudinal clinical studies of project 5 that examine disease progression in PD patients, including psychiatric and cognitive comorbidity. They will provide critical information on the time course of the deficits and new models for projects 2 and 3 and test in an in vivo mammalian system the hypotheses generated in cellular models in project 4 of the Center.

描述（由申请人提供）： 新证据表明，不同的突变通过也可能在散发性帕金森病中发挥作用的机制导致家族性帕金森病（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。 项目1 职务名称： DA细胞死亡前行为和病理缺陷的进展 PD小鼠模型 主要研究者： Marie-Francoise Chesselet，医学博士，哲学博士 描述（由申请人提供）： 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。在目前的资助期间，我们已经在表达已知导致人类PD的各种突变的小鼠中确定了细胞功能障碍，而没有细胞死亡。在这项更新申请中，我们将测试这一假设，即功能障碍的常见机制可能是由不同的突变引起的，并在疾病的早期阶段，在进一步的细胞死亡造成不可逆的损伤之前，为治疗提供治疗靶点。项目1。2.和3构成了当前奖项的延续，并将继续使用多学科方法来揭示现有和新型小鼠模型中神经元功能障碍的机制。在项目1的具体目标1中，我们将确定在不同启动子下过表达α-突触核蛋白的现有小鼠和parkin KO小鼠中行为缺陷和神经病理学的进展。我们将使用我们开发的一系列敏感的运动测试来评估小鼠的运动表型，并将这种分析扩展到非运动行为，因为相关症状可能对患者的生活质量产生重大影响，如中心项目5所述。我们将使用免疫组织化学来确定已知在PD中受影响的多个脑区域中α-突触核蛋白病理学和神经胶质细胞活化的进展，并检测参与神经递质释放的蛋白质表达的异常，并在中心的项目4中进行检查。我们将使用配体结合和分子方法来确定多巴胺能传递的失调，这将在项目2和项目3中分别用神经化学方法和电生理学方法进一步研究。最后，将使用无偏体视学在老年动物中评估PD中受影响的脑区域（蓝斑、腹侧髓质、黑质纹状体多巴胺能神经元）中的最终细胞损失。在具体目标2中，我们将该分析扩展到使用最先进的BAG技术在小鼠遗传学核心中生成的新型小鼠模型。其中包括一个表达帕金突变的小鼠模型，该突变导致果蝇多巴胺能神经元的丧失。在项目2和3中进一步分析之前，将使用上述相同的方法对这些小鼠进行表征。项目1的研究将与项目5的纵向临床研究平行，这些研究检查了PD患者的疾病进展，包括精神和认知共病。他们将为项目2和3提供关于缺陷时间进程和新模型的关键信息，并在体内哺乳动物系统中测试中心项目4中细胞模型产生的假设。