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.

项目概要 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。通过水解酶 β 和 γ 分泌酶调节淀粉样前体蛋白 (APP) 的形成受脑胆固醇影响并取决于蛋白质的聚类。在此应用中，我们建议使用焦点。超声 (FUS) 破坏 APP 胆固醇聚集和炎症调节因子 Toll 样受体 4 (TLR4) 和肿瘤坏死因子 α (TNF𝛼)，它们也是 AD 的促成因素，因为 FUS 可以。逆转 AD 大脑中胆固醇的影响。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 APP 的聚类。以及使用 dSTORM 超分辨率成像在 AD 小鼠模型中使用和不使用 FUS 的伽玛分泌酶。在第二个目标中，我们将表征炎症蛋白 TLR4 和 TNF𝛼 响应 FUS 也在 AD 小鼠模型中。这项工作的前提是胆固醇调节细胞膜中蛋白质的纳米级运输， FUS 破坏了贩运，研究的完成建立了 FUS 的直接分子机制。独立于打开血脑屏障和 FUS 方案，具有预防或阻止 AD 的潜力进展。