Magnetic Resonance Molecular Imaging Studies of Alzheimer's Disease

描述(由申请人提供)：拟议的跨学科研究允许候选人进一步发展他在磁共振(MR)分子成像和阿尔茨海默病(AD)方面的知识和专长，同时提供对研究项目生物医学方面的严格接触。目标是增加候选人在多个领域的专业知识，这些领域是他提议的研究项目和未来职业发展所必需的。这些领域包括神经学、神经退行性疾病、组织学、分子和细胞生物学、光学成像、小动物成像以及造影剂化学合成和表征。该奖项将为候选人成为一名成功的独立研究人员提供必要的指导和培训。阿尔茨海默病研究的一个主要目标是开发反映潜在神经病理过程的定量测量方法。虽然在鉴定脑脊液中的生物标志物方面取得了一些有希望的进展，但它们还不能提供与AD相关的脑变化的直接联系，而AD相关的脑变化将成为治疗干预的目标。这项提议的目的是为神经元结构和功能的特定生物标志物开发磁共振造影剂探针，以提供对AD大脑变化的这种直接测量。特别是，磁共振分子成像技术和造影剂将被开发用于对β-淀粉样蛋白(A-β)和在记忆形成中起关键作用的基因的表达进行体内成像，这些基因已被证明在AD中受到抑制。特征明确的淀粉样前体蛋白(APP)转基因阿尔茨海默病小鼠模型将被用于测试这些新的成像技术和造影剂的有效性。这些研究还将有助于识别和测试调节淀粉样蛋白水平和/或恢复正常基因表达水平的潜在治疗剂。该建议的具体目的是：(1)开发改进的磁共振成像技术，用于靶向氧化铁纳米颗粒分子成像造影剂；(2)开发与A-β特异结合的敏感的氧化铁基造影剂；(3)开发标记氧化铁的寡核苷酸造影剂，使活性调节细胞骨架相关蛋白(Arc)的mRNA表达水平能够成像，Arc是参与神经元结构和功能的重要蛋白质。

DESCRIPTION (provided by applicant): The proposed interdisciplinary study allows the candidate to further develop his knowledge and expertise in magnetic resonance (MR) molecular imaging and Alzheimer's disease (AD), while providing rigorous exposure to the biomedical aspects of the research project. The goal is to increase the candidate's expertise in multiple areas necessary to his proposed research project and future career development. These areas include neurology, neurodegenerative disease, histology, molecular and cellular biology, optical imaging, small animal imaging, and contrast agent chemical synthesis and characterization. This award will provide the guidance and training necessary for the candidate to become a successful, independent researcher. A major goal in Alzheimer's disease research has been to develop quantitative measurements that reflect the underlying neuropathological process. While some promising headway has been made in identifying biomarkers in cerebral spinal fluid, they fall short of providing a direct link to the AD related brain changes that will be the targets of therapeutic intervention. The aim of this proposal is to develop MR contrast agent probes for specific biomarkers of neuronal structure and function that could provide such a direct measure of AD brain changes. In particular, MR molecular imaging techniques and contrast agents will be developed for the in-vivo imaging of beta-amyloid (A-beta) and the expression of genes that play crucial roles in memory formation, which have been shown to be suppressed in AD. Well-characterized Amyloid Precursor Protein (APP) transgenic mouse models of AD will be utilized to test the efficacy of these novel imaging techniques and contrast agents. These studies will also help to identify and test potential therapeutic agents that regulate amyloid levels and/or restore normal gene expression levels. The specific aims of the proposal are to: (1) develop improved MR imaging techniques for imaging targeted iron-oxide nanoparticle based molecular imaging contrast agents; (2) develop sensitive iron-oxide based contrast agents that specifically bind A-beta; (3) develop oligodeoxynucleotide tagged iron-oxide contrast agents that will enable the imaging of mRNA expression levels of activity-regulated cytoskeleton- associated protein (Arc), an important protein involved in neuronal structure and function.