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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

基本信息

批准号：
10541153
负责人：
Kiran Solingapuram Sai
金额：
$ 47.56万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
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/10541153
关键词：
AD transgenic mice APP-PS1 Affinity Aftercare Age Months Alzheimer disease detection Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos 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 Production Reducing Agents Reporting Research Research Personnel Signal Transduction Stabilizing Agents Stratification Structural Protein Tauopathies Techniques Testing Therapeutic Therapeutic Agents Therapeutic Intervention Therapeutic Studies Time Tracer Transgenic Organisms Treatment Protocols Tubular formation Wild Type Mouse Work X-Ray Computed Tomography abeta accumulation 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 neuropathology novel overexpression precision medicine scaffold small molecule standard care targeted treatment tau Proteins tau aggregation tau-1 tool transgenic model of alzheimer disease translational potential treatment strategy uptake

项目摘要

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.

项目总结/文摘