MULTI-DISCIPLINARY APPROACHES FOR PRECLINICAL RESEARCH IN PARKINSONS DISEASE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 当纹状体多巴胺水平下降50%和80%时，帕金森病的临床症状就会出现，黑质内的多巴胺能神经元已经退化(Marsden，1990)。路易体形成是帕金森病神经病理学的一个显著特征，在大脑的几个区域，包括黑质，都有发现。在路易小体中发现了[α]-突触核蛋白聚集体([α]-SYN)(Spillantini等人。1997年；Wakabayashi等人。1997)，这表明[α]-SYN在帕金森病中的作用。Masliah博士和加州大学圣地亚哥分校的同事们在研究阿尔茨海默病时，是最先描述[阿尔法]-SYN的人之一(Iwai等人。1995年；Masliah等人。1996年)。 随着最近发现关键蛋白(如a-SYN)参与帕金森病的发病机制，与人类帕金森病非常相似的转基因小鼠动物模型的发展为研究预防或逆转与帕金森病相关的神经退行性变的策略提供了新的机会。这项拟议的工作是及时的，因为我们的小组最近制作了一种PD的动物模型(Rockenstein等人)，并部分描述了该模型的特征。2002年)。这些小鼠是通过基因工程过表达α-突触核蛋白的，α-突触核蛋白是帕金森患者中枢神经系统中蛋白质聚集体的关键成分。在与NCMIR科学家的合作下，我们正在通过对这种PD转基因动物模型进行广泛的成像研究来扩展我们最初的观察结果。这些研究的结果将被整合到神经成像信息数据库中，以便于定量比较化疗药物在正常和类PD疾病状态下的效果。选定的成像方法使我们能够覆盖从整个大脑到超分子复合体的范围，并在其亚细胞位置识别特定的蛋白质。 通过BIRN-促进科学发现的合作努力：随着生物信息学方法和工具集成到BIRN门户用户界面中，研究人员将能够提出新的问题，从而推动NCMIR的成像技术能力，以满足他们日益增长的研究需求。NCMIR提供最先进的设施、经验丰富的员工以及无与伦比的仪器和计算机科学开发团队成员。BIRN项目的启动也带来了与NCRR资助的其他资源(例如，与杜克大学G.Allan Johnson博士的显微核磁共振合作)。BIRN的基层纳入给了我们独特的机会，将这个以NCMIR为中心的项目用作框架，将人类疾病的小鼠模型纳入BIRN的小鼠组件(MBIRN)。我们正在利用这个机会向该领域的其他研究人员展示这种类型的合作研究的优势，这将有助于增加NCMIR的合作项目。 项目目标：该项目致力于开发和应用帕金森氏病(PD)的相关成像方法--首先应用于最近产生的帕金森氏病转基因动物模型。从这个项目中获得的知识将有助于评估帕金森病的神经病理和可能的化疗治疗的有效性。 该项目的具体目标是： 1.从三个水平表征转基因a-SYN小鼠和年龄匹配的对照组小鼠的表型差异： +总水平 +区域/蜂窝级别 +高分辨率分子组成分布图 2.将这些转基因动物的多尺度和多模式数据整合到生物医学信息学研究网络(BIRN)中 3.与其他帕金森病研究小组建立合作关系，并将更多的动物模型纳入BIRN帕金森病研究组合进行比较。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The presentation of clinical symptoms of PD occurs when striatal dopamine levels decrease by 50% and 80% of dopaminergic (DA) neurons within the substantia nigra have degenerated (Marsden 1990). Lewy body formations, a hallmark feature of PD neuropathology, are found in several areas of the brain including the substantia nigra. Aggregates of [alpha]-synuclein ([alpha]-SYN) are found within Lewy Bodies (Spillantini et al. 1997; Wakabayashi et al. 1997), which suggests a role for [alpha]-SYN in PD. Dr. Masliah and colleages at UC San Diego was among the first to characterize [alpha]-SYN while working on Alzheimer's disease (Iwai et al. 1995; Masliah et al. 1996). Together with recent discoveries of involvement of key proteins (like a-SYN) in the pathogenesis of PD, the development of transgenic mouse animal models that closely resemble human PD are providing new opportunities to study strategies to prevent or reverse the neurodegeneration associated with PD. The proposed work is timely as our group has recently produced, and partially characterized an animal model of PD (Rockenstein et al. 2002). These mice are genetically engineered to overexpress alpha-synuclein, which is a key component of protein aggregates found in the CNS of Parkinsonian patients. In collaboration with NCMIR scientists, we are extending our original observations by conducting extensive imaging studies on this transgenic animal model of PD. The results of these studies will be integrated into a database of neuroimaging information to facilitate quantitative comparisons of the effects of chemotherapeutic agents in normal and PD-like disease states. The selected imaging methods allow us to cover the scales from whole brain to supramolecular complexes, with specific proteins identified in their subcellular locations. Collaborative efforts via BIRN - Facilitation of scientific discovery: With bioinformatics methods and tools integrated into the BIRN portal user interface, researchers will be able to ask new questions, thereby driving the imaging technologies capabilities at NCMIR to meet the increasing demands of their research. The NCMIR offers state of the art facilities, experienced staff, and unparalleled instrumentation and computer science development team members. The inception of the BIRN project has also brought additional opportunities for collaborative efforts with other NCRR-funded resources (ex. microscopic MRI collaboration with Dr. G. Allan Johnson at Duke University). Ground level inclusion into the BIRN has given us the unique opportunity to bring this NCMIR-centered project to use as framework for inclusion of a mouse model of human disease into the mouse component of the BIRN (MBIRN). We are using this opportunity to demonstrate the advantages of this type of collaborative research to other researchers in the field, which will serve to increase collaborative projects at NCMIR. Project Aims: The project efforts are focused on the development and application of correlated imaging approaches to Parkinson's Disease (PD) - applied first to a recently generated transgenic animal model of PD. Knowledge gained from this project will facilitate the assessment of neuropathologies and effectiveness of possible chemotherapeutic treatments for PD. The specific goals of this project are: 1. To characterize the phenotypic differences between transgenic a-SYN and age-matched control mice at three levels: +Gross level +Regional/cellular level +High resolution distribution maps of molecular constituents 2. To integrate multi-scale and multi-modal data from these transgenic animals into the Biomedical Informatics Research Network (BIRN) 3. To establish collaborations with other PD research groups, and bring additional animal models into the BIRN PD portfolio for comparison.