MULTI-DISCIPLINARY APPROACHES FOR PRECLINICAL RESEARCH IN PARKINSONS DISEASE

帕金森病临床前研究的多学科方法

• 批准号: 7722433
• 负责人: ELIEZER MASLIAH
• 金额: $ 2.44万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7722433
• 关键词: Age; Alzheimer' s Disease; Animal Model; Area; Arts; Automobile Driving; Bioinformatics; Biomedical Informatics Research Network; Brain; Clinical; Collaborations; Complex; Computer Retrieval of Information on Scientific Projects Database; Corpus striatum structure; Data; Databases; Development; Disease; Dopamine; Effectiveness; Funding; Genetically Engineered Mouse; Goals; Grant; Human; Image; Imaging technology; Institution; Knowledge; Lewy Bodies; Location; Magnetic Resonance Imaging; Maps; Methods; Microscopic; Molecular; Mus; Nerve Degeneration; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Patients; Protein Overexpression; Proteins; Research; Research Personnel; Resolution; Resources; Role; Scientist; Source; Substantia nigra structure; Symptoms; Transgenic Animals; Transgenic Mice; Transgenic Organisms; United States National Institutes of Health; Universities; Work; alpha synuclein; chemotherapeutic agent; computer science; dopaminergic neuron; experience; human disease; instrumentation; member; mouse model; neuroimaging; neuropathology; pre-clinical research; prevent; protein aggregate; tool

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.

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 当纹状体多巴胺水平降低50%且黑质内80%的多巴胺能（DA）神经元变性时，PD的临床症状出现（Marsden 1990）。 路易体形成是PD神经病理学的标志性特征，在包括黑质在内的脑的几个区域中发现。 在路易小体中发现[α]-突触核蛋白（[α]-SYN）的聚集体（Spillantini et al. 1997; Wakabayashi et al. 1997），这表明[α]-SYN在PD中的作用。 加州大学圣地亚哥分校的Masliah博士和同事们是在研究阿尔茨海默病时最早描述[alpha]-SYN的人之一（Iwai et al. 1995; Masliah et al. 1996）。 与最近发现的参与PD发病机制的关键蛋白质（如α-SYN）一起，与人类PD非常相似的转基因小鼠动物模型的开发为研究预防或逆转与PD相关的神经变性的策略提供了新的机会。 由于我们小组最近制作了PD动物模型并对其进行了部分表征，因此建议的工作是及时的（Rockenstein et al. 2002）。 这些小鼠经过基因工程改造，过表达α-突触核蛋白，这是帕金森病患者CNS中发现的蛋白质聚集体的关键成分。与NCMIR科学家合作，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影像学信息的数据库中，以便于定量比较化疗药物在正常和PD样疾病状态下的作用。 所选择的成像方法使我们能够覆盖从全脑到超分子复合物的尺度，并在其亚细胞位置识别特定蛋白质。 通过BIRN的合作努力-促进科学发现：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，以满足其日益增长的研究需求。 NCMIR提供最先进的设施，经验丰富的工作人员，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其他国家人权委员会资助的资源（例如：显微镜下的核磁共振成像合作。艾伦约翰逊在杜克大学）。 纳入BIRN的基础水平为我们提供了独特的机会，使这个以NCMR为中心的项目用作将人类疾病的小鼠模型纳入BIRN（MBIRN）小鼠部分的框架。 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：该项目的工作重点是开发和应用相关的成像方法，帕金森病（PD）-首先应用于最近产生的转基因动物模型的PD。 从这个项目中获得的知识将有助于评估神经病理学和可能的PD化疗治疗的有效性。 该项目的具体目标是： 1. 在三个水平上表征转基因a-SYN和年龄匹配的对照小鼠之间的表型差异： +毛额 +区域/单元一级 +高分辨率分子组分分布图 2. 将这些转基因动物的多尺度和多模态数据整合到生物医学信息学研究网络（BIRN）中 3. 与其他PD研究小组建立合作，并将其他动物模型纳入BIRN PD组合进行比较。