MULTI-DISCIPLINARY APPROACHES FOR PRECLINICAL RESEARCH IN PARKINSONS DISEASE

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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.