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: 7612088
• 负责人: CHRISTIAN T FARRAR
• 金额: $ 15.31万
• 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/7612088
• 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; Complex; 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; 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; base; career development; chemical synthesis; efficacy testing; 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）：拟议的跨学科研究使候选人能够进一步发展其磁共振（MR）分子成像和阿尔茨海默氏病（AD）的知识和专业知识，同时为研究项目的生物医学方面提供了严格的暴露。目的是提高候选人在其拟议的研究项目和未来职业发展所需的多个领域的专业知识。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，小动物成像以及对比剂化学合成和表征。该奖项将为候选人成为成功的独立研究人员提供必要的指导和培训。阿尔茨海默氏病研究的主要目标是开发反映基本神经病理过程的定量测量。虽然在识别脑脊柱液中的生物标志物方面已经取得了一些有希望的进展，但它们没有提供与AD相关的大脑变化的直接联系，这将是治疗性干预的靶标。该提案的目的是开发MR对比剂探针，以针对神经元结构和功能的特定生物标志物进行这种直接衡量的AD脑变化。特别是，将开发MR分子成像技术和对比剂，以用于β-淀粉样β（A-BETA）的体内成像以及在记忆形成中起着至关重要的作用的基因的表达，这些基因已被证明在AD中被抑制。特征良好的淀粉样蛋白前体蛋白（APP）AD的转基因小鼠模型将用于测试这些新型成像技术和对比剂的功效。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）开发改进的MR成像技术，用于成像靶向的铁氧化物纳米颗粒的分子成像对比剂； （2）开发具有特异性结合A-beta的敏感铁氧化对比剂； （3）开发寡脱氧核苷酸标记的铁氧化物对比剂，该剂将使活性调节的细胞骨架相关蛋白（ARC）的mRNA表达水平成像，这是一种参与神经元结构和功能的重要蛋白质。