Evaluating microtubule binding as a potential imaging biomarker for Alzheimer's disease

评估微管结合作为阿尔茨海默病的潜在成像生物标志物

• 批准号: 10083685
• 负责人: Kiran Solingapuram Sai
• 金额: $ 53.6万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10083685
• 关键词: AD transgenic mice; APP-PS1; Affinity; Aftercare; Age-Months; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer’s disease biomarker; Amyloid beta-Protein; Attention; Autoradiography; Axonal Transport; Binding; Biochemical; Biodistribution; Biological Assay; Biological Markers; Brain; Cessation of life; Clinical; Clinical Treatment; Clinical Trials; Cognitive; Cytoskeleton; Data; Dependence; Disease; Disease Progression; Early Diagnosis; Future; Glioblastoma; Goals; Image; Impaired cognition; Impairment; In Vitro; Laboratories; Magnetic Resonance Imaging; Malignant neoplasm of brain; Measures; Methods; Microtubule stabilizing agent; Microtubules; Modality; Mus; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Positron-Emission Tomography; Process; Reducing Agents; Reporting; Research; Research Personnel; Senile Plaques; Signal Transduction; Stabilizing Agents; Stratification; Structural Protein; Structure; Tauopathies; Techniques; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Therapeutic Studies; Time; Tracer; Transgenic Organisms; Translations; Treatment Protocols; Wild Type Mouse; Work; X-Ray Computed Tomography; abeta accumulation; base; beta amyloid pathology; clinical imaging; clinically relevant; cohort; density; diagnostic biomarker; extracellular; human subject; hyperphosphorylated tau; imaging agent; imaging biomarker; imaging properties; imaging study; improved; in vivo; in vivo imaging; innovation; microPET/CT; mouse model; nervous system disorder; neuroimaging; novel; overexpression; precision medicine; scaffold; small molecule; standard care; targeted treatment; tau Proteins; tau aggregation; tau phosphorylation; tool; treatment strategy; uptake

Project Summary/Abstract Impairment of neuronal microtubules resulting from hyper-phosphorylation of the tau proteins is implicated in many disease pathologies including Alzheimer's disease (AD), Parkinson disease and other neurological disorders. However, there techniques. (PET) indicates neurodegeneration way are no reliable noninvasive methods to quantify microtubules using clinical imaging key unanswered question is whether the quantitative nature of Positron Emission Tomography harnessed to measure in vivo concentrations of microtubules. Increasing scientific evidence microtubule stabilizing agents provides protective benefits against the deleterious effects of in treating AD. However, quantifying these protective benefits is difficult, since there is no to directly probe their interactions with microtubules. A can be that Our goal is to develop in vivo imaging of microtubules using our novel PET probes, at all stages of AD progression. Thus we propose 3 Specific Aims based on our strong preliminary data. In Aim 1, we will determine the relationship between microtubule integrity and amyloid β pathology by performing longitudinal microPET/CT imaging of microtubules with [11C]MPC-6827 and amyloid β imaging with [11C]PiB in two murine models of AD. In Aim 2, we will quantify and characterize microtubule uptake in brains of the same murine models of AD using [3H]/[11C]MPC-6827. We will perform ex vivo biodistribution, in vitro autoradiography and histopathological assays to correlate microtubule density with routine neurobiomarkers. In Aim 3, we will determine and establish dependency of microtubule imaging uptake to amyloid β and/or tau levels after therapeutic interventions. We will perform microPET/CT images in the same two murine models of AD, before, during and after the standard treatment protocols with potential therapeutic agents reducing amyloid β and/or tau levels. In this project, led by an Early Stage Investigator, we hypothesize that we can expand the microtubule scaffold as potential in vivo imaging agents, not only to diagnose AD at an early stage, but also follow the therapeutic utility of the treatments. The PET imaging data generated could be a valuable tool for clinicians to assess AD in several stages of progression and treatment. This project is the first to propose the imaging of microtubules in vivo in AD. If successful, this work will provide a new paradigm to directly probe microtubules in vivo in real time. Our work could markedly enhance precision medicine approaches for treatment of AD and other neurodegenerative diseases.

项目概要/摘要 tau 蛋白过度磷酸化导致的神经元微管损伤与 许多疾病病理，包括阿尔茨海默病 (AD)、帕金森病和其他神经系统疾病 然而，有障碍。 技术。 （宠物） 表示 神经变性 方式 没有可靠的非侵入性方法来使用临床成像量化微管 尚未解答的关键问题是正电子发射断层扫描的定量性质是否 越来越多的科学证据用于测量微管的体内浓度。 微管稳定剂提供保护作用，防止有害影响 然而，量化这些保护作用是很困难的，因为没有。 直接探测它们与微管的相互作用。 一个 可以是 那 我们的目标是开发微管的体内成像 在 AD 进展的所有阶段使用我们的新型 PET 探针，因此我们根据我们的研究提出了 3 个具体目标。 在目标 1 中，我们将确定微管完整性和淀粉样蛋白之间的关系。 通过使用 [11C]MPC-6827 和淀粉样蛋白对微管进行纵向 microPET/CT 成像来观察β病理学 在两种 AD 小鼠模型中使用 [11C]PiB 进行 β 成像 在目标 2 中，我们将量化和表征微管。 我们将使用 [3H]/[11C]MPC-6827 在相同 AD 小鼠模型的大脑中进行摄取。 生物分布、体外放射自显影和组织病理学测定将微管密度与 在目标 3 中，我们将确定并建立微管成像摄取的依赖性。 我们将在治疗干预后对β淀粉样蛋白和/或 tau 蛋白水平进行 microPET/CT 成像。 相同的两个AD小鼠模型，在标准治疗方案之前、期间和之后具有潜在的潜力 降低淀粉样蛋白 β/或 tau 水平的治疗药物 在这个由早期研究人员领导的项目中，我们。 追求我们可以扩展微管支架作为潜在的体内成像剂，不仅是为了 在早期诊断 AD，同时还要跟踪治疗的治疗效果。 生成的结果可能是忠诚者评估 AD 各个进展和治疗阶段的宝贵工具。 该项目是第一个提出 AD 体内微管成像的项目。如果成功，这项工作将提供。 我们的工作可以显着提高实时体内微管的新范例。 治疗 AD 和其他神经退行性疾病的医学方法。