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Regulation of amyloid production by focused ultrasound

聚焦超声调节淀粉样蛋白的产生

基本信息

批准号：
10511752
负责人：
Scott B Hansen
金额：
$ 51.52万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10511752
关键词：
Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model American Amyloid Amyloid Proteins Amyloid beta-Protein Amyloid beta-Protein Precursor Animals Blood - brain barrier anatomy Brain Cholesterol Collaborations Disease Progression Environment Enzymes Focused Ultrasound Ganglioside GM1 Image Individual Inflammasome Inflammation Inflammatory Label Lipids Mechanics Membrane Microbubbles Molecular Monitor Movement Mus Neurodegenerative Disorders Physics Production Proteins Protocols documentation Regulation Research Research Institute Resolution Signal Transduction Slice Sonication TLR4 gene TNF gene Techniques Testing Work amyloid formation beta secretase biophysical techniques brain tissue cost experience gamma secretase genetic risk factor mechanical force mouse model nanoscale neuroinflammation prevent protein aggregation protein function protein transport response secretase shear stress tool trafficking ultrasound

项目摘要

PROJECT SUMMARY Beta amyloid (Aβ) is a protein that aggregates to form plaques associated with Alzheimer disease (AD). Its formation from amyloid precursor protein (APP) by hydrolytic enzymes beta and gamma secretases is regulated by brain cholesterol and depends on clustering of the proteins. In this application we propose to use focus ultrasound (FUS) to disrupt cholesterol’s clustering of APP and inflammatory regulators toll like receptor 4 (TLR4) and tumor necrosis factor alpha (TNF𝛼) which are also contributors to AD. We hypothesize, in that FUS can reverse the effects cholesterol in an AD brain. To test our hypothesis, we propose two specific aims. First, we will analyze clustering of amyloid proteins APP and gamma secretase with and without FUS using dSTORM super resolution imaging in a mouse model of AD. In a second aim we will characterize the de-clustering of inflammatory proteins TLR4 and TNF𝛼 in response to FUS also in an AD mouse model. The premise of this work is that cholesterol regulates nanoscopic trafficking of proteins in the membrane and FUS disrupts the trafficking. Completion of the studies establish a direct molecular mechanism for FUS independent of opening the blood brain barrier and FUS protocols with the potential to prevent or stop AD progression.

项目摘要 β淀粉样蛋白（Aβ）是一种聚集形成与阿尔茨海默病（AD）相关的斑块的蛋白质。其通过水解酶β和γ分泌酶从淀粉样前体蛋白（APP）形成受到调节由脑胆固醇和蛋白质的聚集决定。在这个应用程序中，我们建议使用焦点超声波（FUS）破坏APP和炎症调节因子Toll样受体4（TLR4）的胆固醇聚集和肿瘤坏死因子α（TNFα），它们也是AD的贡献者。我们假设，FUS可以逆转胆固醇对AD大脑的影响为了验证我们的假设，我们提出了两个具体目标。首先，我们将分析淀粉样蛋白APP的聚类和γ分泌酶，使用dSTORM超分辨率成像在AD的小鼠模型中使用和不使用FUS。在第二个目标中，我们将描述炎症蛋白TLR4和TNFα的去聚集反应， FUS也在AD小鼠模型中。这项工作的前提是，胆固醇调节膜中蛋白质的纳米级运输， FUS破坏了贩运。研究的完成确立了FUS的直接分子机制独立于开放血脑屏障和FUS方案，具有预防或阻止AD的潜力进展