Magnetic Resonance Molecular Imaging Studies of Alzheimer's Disease

阿尔茨海默病的磁共振分子成像研究

• 批准号: 7321368
• 负责人: CHRISTIAN T FARRAR
• 金额: $ 15.15万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7321368
• 关键词: Affinity; Alzheimer' s Disease; Amphetamines; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animals; Antibodies; Area; Award; Binding; Biodistribution; Biological Markers; Blood - brain barrier anatomy; Brain; Brain imaging; Brain region; Cells; Cerebrospinal Fluid; Cerebrum; Chemicals; Clinical; Confocal Microscopy; Congo Red; Contrast Media; Cytoskeleton; Detection; Development; Diagnostic; Diffuse; Early Diagnosis; Exposure to; Failure; Focused Ultrasound Therapy; Functional disorder; Future; Gene Expression; Genes; Goals; Histology; Image; Imaging Techniques; Immediate-Early Genes; Immunohistochemistry; In Vitro; Injection of therapeutic agent; Interdisciplinary Study; Invasive; Knowledge; Leg; Life; Link; Magnetic Resonance; Magnetic Resonance Imaging; Maintenance; Mannitol; Measurement; Measures; Memory; Messenger RNA; Methods; Molecular; Molecular and Cellular Biology; Monitor; Mus; Nature; Neurodegenerative Disorders; Neurology; Neurons; Play; Predisposition; Process; Proteins; Research; Research Personnel; Research Project Grants; Resolution; Role; Senile Plaques; Sensitivity and Specificity; Specimen; Staging; Staining method; Stains; Structure; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Tissues; Training; Transcript; Transgenic Mice; Transgenic Organisms; base; career; chemical synthesis; falls; improved; in vivo; inhibitor/antagonist; insight; interest; iron oxide; mRNA Expression; molecular imaging; mouse model; nanoparticle; neuron loss; novel; optical imaging; secretase; tissue culture

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.

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）方面的知识和专业知识，同时提供对研究项目的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，这些领域对他提出的研究项目和未来的职业发展是必要的。这些领域包括神经病学、神经退行性疾病、组织学、分子和细胞生物学、光学成像、小动物成像和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。虽然在确定脑脊液中的生物标志物方面取得了一些有希望的进展，但它们未能提供与AD相关脑变化的直接联系，而AD相关脑变化将是治疗干预的目标。该提案的目的是开发用于神经元结构和功能的特定生物标志物的MR造影剂探针，其可以提供AD脑变化的直接测量。特别是，MR分子成像技术和造影剂将被开发用于β-淀粉样蛋白（A-β）的体内成像和在记忆形成中起关键作用的基因的表达，这些基因已被证明在AD中受到抑制。将利用充分表征的淀粉样前体蛋白（APP）转基因AD小鼠模型来测试这些新型成像技术和造影剂的功效。这些研究还将有助于鉴定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。该提案的具体目的是：（1）开发用于对靶向的基于氧化铁纳米颗粒的分子成像造影剂进行成像的改进的MR成像技术;（2）开发特异性结合A-β的敏感的基于氧化铁的造影剂;（3）开发寡脱氧核苷酸标记的氧化铁造影剂，其将使得能够对活性调节的细胞骨架相关蛋白（Arc）的mRNA表达水平成像，参与神经元结构和功能的重要蛋白质。