MULTI-DISCIPLINARY APPROACHES FOR PRECLINICAL RESEARCH IN PARKINSONS DISEASE

帕金森病临床前研究的多学科方法

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

该子项目是利用该技术的众多研究子项目之一资源由 NIH/NCRR 资助的中心拨款提供。子项目和研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金，因此可以在其他 CRISP 条目中表示。列出的机构是对于中心来说，它不一定是研究者的机构。当纹状体多巴胺水平下降 50% 且黑质内 80% 的多巴胺能 (DA) 神经元退化时，就会出现 PD 的临床症状 (Marsden 1990)。路易体结构是帕金森病神经病理学的标志性特征，存在于包括黑质在内的大脑多个区域。在路易体内发现了 α-突触核蛋白 (α-SYN) 的聚集体 (Spillantini 等人 1997；Wakabayashi 等人 1997)，这表明 α-SYN 在 PD 中发挥作用。 Masliah 博士和加州大学圣地亚哥分校的同事在研究阿尔茨海默氏病时是最早表征 α-SYN 的人之一(Iwai 等人，1995；Masliah 等人，1996)。加上最近发现关键蛋白（如 a-SYN）参与 PD 发病机制，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 相关的神经变性策略提供了新的机会。这项工作是及时的，因为我们的小组最近制作了 PD 动物模型，并对其进行了部分表征（Rockenstein 等人，2002）。这些小鼠经过基因工程改造，过度表达α-突触核蛋白，这是帕金森病患者中枢神经系统中蛋白质聚集体的关键成分。我们与 NCMIR 科学家合作，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信息数据库中，以便于定量比较化疗药物在正常和PD样疾病状态下的效果。所选的成像方法使我们能够覆盖从全脑到超分子复合物的范围，并在其亚细胞位置鉴定出特定的蛋白质。通过 BIRN 进行协作 - 促进科学发现：通过将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 项目的启动还带来了与其他 NCRR 资助的资源合作的更多机会（例如与杜克大学的 G. Allan Johnson 博士进行显微 MRI 合作）。 BIRN 的地面纳入为我们提供了独特的机会，可以将这个以 NCMIR 为中心的项目用作将人类疾病小鼠模型纳入 BIRN (MBIRN) 小鼠组件的框架。我们利用这个机会向该领域的其他研究人员展示此类合作研究的优势，这将有助于增加 NCMIR 的合作项目。项目目标：该项目的重点是帕金森病 (PD) 相关成像方法的开发和应用 - 首先应用于最近生成的 PD 转基因动物模型。从该项目中获得的知识将有助于评估神经病理学和帕金森病可能的化疗治疗的有效性。该项目的具体目标是： 1. 在三个水平上表征转基因 a-SYN 和年龄匹配对照小鼠之间的表型差异： +毛水平 +区域/蜂窝级别 +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、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，并将更多动物模型纳入BIRN PD组合中进行比较。