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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 当纹状体多巴胺水平降低50％和80％的多巴胺能（DA）神经元中，NIGRA中的纹状体多巴胺水平降低了50％和80％（Marsden 1990）时，PD的临床症状呈现（Marsden 1990）。 Lewy身体地层是PD神经病理学的标志性特征，在大脑的多个区域都可以找到Nigra。 [alpha] -synclein（[alpha] -syn）的聚集体在Lewy体内（Spillantini等，1997; Wakabayashi etal。1997），这暗示了[alpha] -syn在PD中的作用。 马斯利亚博士和圣地亚哥分校的寓言是最早在阿尔茨海默氏病工作时表征[alpha] -syn的人之一（Iwai等，1995； Masliah等，1996）。 加上最近发现关键蛋白（如A-Syn）参与PD发病机理的发现，与人类PD紧密相似的转基因小鼠动物模型的发展正在为研究与PD相关的神经变性的策略提供新的机会。 拟议的工作是及时的，正如我们的小组最近生产的那样，部分表征了PD的动物模型（Rockenstein等，2002）。 这些小鼠在遗传上设计为过表达α-核蛋白，这是帕金森患者中枢神经系统中发现的蛋白质聚集体的关键组成部分。与NCMIR科学家合作，我们通过对PD的转基因动物模型进行广泛的成像研究来扩展我们的原始观察结果。 这些研究的结果将集成到神经影像信息的数据库中，以促进化学治疗剂在正常和PD样疾病状态下的作用的定量比较。 所选的成像方法使我们能够覆盖从整个大脑到超分子复合物的尺度，并在其亚细胞位置鉴定出特定的蛋白质。 通过BIRN进行的协作努力 - 科学发现的促进：通过将生物信息学方法和工具集成到Birn Portal用户界面中，研究人员将能够提出新的问题，从而在NCMIR的Imaging Technologies功能中推动成像技术的能力，以满足他们不断增长的研究需求。 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项目的启动还为与其他NCRR资助的资源（EX。MIRSCOPICMRI与G. Allan Johnson博士合作）为合作提供了更多机会。 将BIRN的地面加入给我们带来了独特的机会，将以NCMIR为中心的项目作为将人类疾病小鼠模型纳入BIRN（MBIRN）的框架。 我们正在利用这一机会向该领域的其他研究人员展示此类协作研究的优势，这将有助于增加NCMIR的协作项目。 项目的目的：项目工作的重点是首先应用于最近生成的PD转基因动物模型的相关成像方法（PD）的开发和应用。 从该项目中获得的知识将有助于评估神经病理学和PD化学治疗方法的有效性。 该项目的具体目标是： 1。表征转基因A-Syn和年龄匹配的对照小鼠之间的表型差异：三个级别： +总水平 +区域/细胞水平 +分子成分的高分辨率分布图 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PD研究小组建立合作，并将其他动物模型带入BIRN PD投资组合以进行比较。