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）是一种蛋白质，该蛋白质聚集形成与阿尔茨海默氏病（AD）相关的斑块。由水解酶β和伽马分泌酶从淀粉样蛋白前体蛋白（APP）形成通过脑胆固醇，取决于蛋白质的聚类。在此应用程序中，我们建议使用焦点超声（FUS）破坏胆固醇的应用程序和炎症调节器的聚类，例如受体4（TLR4）和肿瘤坏死因子α（TNF𝛼）也是AD的贡献者。我们假设，那个FUS可以扭转AD大脑中胆固醇的作用。为了检验我们的假设，我们提出了两个具体目标。首先，我们将分析淀粉样蛋白应用程序的聚类在AD的小鼠模型中使用DSTORM超级分辨率成像，带有和不使用FUS的Gamma泌尿酶。在第二个目的中，我们将表征炎症蛋白TLR4和TNF𝛼的去聚类 FUS也在AD鼠标模型中。这项工作的前提是，胆固醇调节膜上蛋白质的纳米型贩运 FUS破坏了贩运。研究的完成建立了直接的分子机制独立于打开血脑屏障和FUS方案，以防止或阻止AD 进展。