Treatment of Alzheimer’s Disease using Ultrasound-Targeted Microbubble Cavitation-Mediated Blood Brain Barrier Opening to Facilitate Drug Delivery to the Brain
使用超声靶向微泡空化介导的血脑屏障打开促进药物输送到大脑来治疗阿尔茨海默病
基本信息
- 批准号:10710373
- 负责人:
- 金额:$ 5.27万
- 依托单位:
- 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:2022-07-27 至 2027-07-26
- 项目状态:未结题
- 来源:
- 关键词:AddressAdherens JunctionAdverse effectsAffectAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAmericanAntibodiesAreaAstrocytesBiologyBlood - brain barrier anatomyBlood VesselsBlood capillariesBrainCalciumCaregiversCellsCentral Nervous SystemCoculture TechniquesCombined Modality TherapyConfocal MicroscopyContrast MediaCytoskeletonData AnalysesDepositionDevelopmentDextransDiseaseDoseDrug Delivery SystemsDrug DesignDrug ModelingsDrug usageElectrical ResistanceEndothelial CellsEndotheliumEnzymesEventExperimental DesignsFDA approvedFailureFamilyGoalsHealthcare SystemsImageImpaired cognitionIn VitroIntravenousLiverMediatingMentorsMicrobubblesMicrobubbles Ultrasound Contrast MediumMicrocirculationModelingMolecularMonitorMusNervous SystemNeurodegenerative DisordersPatientsPenetrationPermeabilityPharmaceutical PreparationsPharmacologyPharmacotherapyPhase I Clinical TrialsPhase II Clinical TrialsPhysiciansPhysicsPhysiologyPittsburgh Compound-BPlasmaPositron-Emission TomographyProteinsResearch Project GrantsScientistSignal TransductionSiteStatistical Data InterpretationStressStructureSuspensionsTechniquesTestingTherapeuticTight JunctionsTrainingTranslational ResearchUltrasonic TransducerUmbilical veinaging populationbench-to-bedside translationbeta-site APP cleaving enzyme 1blood-brain barrier permeabilizationbrain circulationbrain endothelial cellcareercareer developmentclinical translationcognitive abilitycognitive functiondesignexperimental studyhuman old age (65+)improvedin vivoinhibitorinsightmeetingsmouse modelmultidisciplinarynervous system disordernovel therapeutic interventionnovel therapeuticsside effectsonoporationsymptom managementtheranosticstherapeutic candidateultrasound
项目摘要
PROJECT SUMMARY/ABSTRACT
Alzheimer’s disease (AD) is a devastating, progressive, neurodegenerative disease that affects millions of
Americans, yet there is no cure, and there are very limited treatment options. Failure of otherwise promising
drugs for AD may be due, in part, to poor penetration into the brain and/or large systemic dose requirements to
achieve therapeutic brain concentrations, resulting in off-target effects. To address blood brain barrier (BBB)
impenetrability, ultrasound-targeted microbubble cavitation (UTMC) is being explored as a new treatment
strategy for AD. In this approach, low intensity ultrasound is applied to intravenously injected ultrasound contrast
agents (microbubbles) as they traverse the microcirculation of the brain. UTMC causes transient endothelial
barrier hyperpermeability, allowing for site-specific delivery of therapeutics across the BBB. While UTMC shows
promise as a technique to increase BBB permeability, its underlying mechanisms are incompletely understood,
ultimately constraining clinical translation. My overarching goal is that UTMC directed to the brain offers an
approach to enhance drug delivery across the BBB for treatment of AD. To facilitate clinical translation of this
platform, my proposal will determine mechanisms mediating UTMC-induced BBB hyperpermeability and utilize
UTMC for delivering therapeutics directed at Ab plaques in vivo in the following Aims: (1) To identify
mechanisms by which UTMC causes transient BBB hyperpermeability. UTMC applied to umbilical vein
endothelial cells in vitro has been shown to change cytoskeletal dynamics, leading to inter-endothelial cell gaps,
which can increase paracellular permeability, and was associated with Ca2+ influx into cells in contact with, and
remote from, cavitating microbubbles. Extending these findings to the BBB, I hypothesize that UTMC-mediated
Ca2+ influx disrupts tight and adherens junctions between brain microvascular endothelial cells, and may also
lead to Ca2+-mediated changes in adjacent astrocytes. A contact co-culture in vitro transwell model of the BBB
will be used to study changes in function and structure (confocal microscopy) of endothelial cells and astrocytes
after UTMC. (2) To determine whether UTMC-mediated BBB opening, in combination with drug therapy,
will lower Ab plaque burden and improve the therapeutic window. I hypothesize that UTMC-mediated BBB
opening will decrease the dose required for a specific drug designed to lower Ab plaque deposition, thereby
minimizing off-target effects. The drug will be administered, and UTMC will be applied to the brain in a mouse
model of AD. Brain Ab plaques will be quantified by serial brain PET imaging. I have assembled an exceptional
multidisciplinary team of mentors and collaborators, along with specific coursework and seminars, to acquire the
necessary content expertise in AD biology, ultrasound theranostics, imaging, and murine AD models. Through
meetings with my mentors and conducting my experiments, I will acquire experiential lessons in rigorous
experimental design, data analysis, and presentation. My comprehensive training plan will prepare me to
achieve my career goal of becoming a physician-scientist pursuing bench to bedside translational research.
项目摘要/摘要
阿尔茨海默病(AD)是一种破坏性的、进行性的神经退行性疾病,影响数百万人,
美国人,但没有治愈,有非常有限的治疗选择。其他承诺的失败
治疗AD的药物可能部分是由于对大脑的渗透性差和/或需要大的全身剂量,
达到治疗脑浓度,导致脱靶效应。解决血脑屏障(BBB)问题
不可穿透性,超声靶向微泡空化(UTMC)正在探索作为一种新的治疗方法
AD战略。在这种方法中,低强度超声应用于静脉注射超声造影剂
药物(微泡),因为它们穿过大脑的微循环。UTMC导致短暂性内皮
屏障通透性过高,允许治疗剂穿过BBB的位点特异性递送。虽然UTMC显示
作为一种有望增加BBB通透性的技术,其潜在机制尚未完全了解,
最终限制了临床翻译。我的首要目标是,UTMC针对大脑提供了一个
这是一种增强药物通过BBB递送以治疗AD的方法。为了便于临床翻译,
平台,我的建议将确定介导UTMC诱导的BBB通透性过高的机制,并利用
UTMC用于在体内递送针对Ab斑块的治疗剂,目的如下:(1)鉴定
UTMC引起短暂BBB通透性过高的机制。UTMC应用于脐静脉
体外内皮细胞已被证明会改变细胞骨架动力学,导致内皮细胞间间隙,
它可以增加细胞旁通透性,并与Ca 2+内流进入接触细胞有关,
远离空化微泡。将这些发现扩展到BBB,我假设UTMC介导的
Ca 2+内流破坏脑微血管内皮细胞之间的紧密和粘附连接,
导致邻近星形胶质细胞中Ca 2+介导的变化。血脑屏障的体外transwell接触共培养模型
将用于研究内皮细胞和星形胶质细胞功能和结构的变化(共聚焦显微镜)
在UTMC之后(2)为了确定UTMC介导的BBB开放是否与药物治疗联合,
将降低Ab斑块负荷并改善治疗窗。我推测UTMC介导的血脑屏障
开放将减少设计用于降低Ab斑块沉积的特定药物所需的剂量,从而
最小化脱靶效应。将给予药物,并将UTMC应用于小鼠的大脑
AD模型将通过连续脑PET成像定量脑Ab斑块。我召集了一个特殊的
导师和合作者的多学科团队,沿着具体的课程和研讨会,以获得
AD生物学、超声治疗诊断学、成像和鼠AD模型方面的必要内容专业知识。通过
会议与我的导师和进行我的实验,我将获得经验教训,严格
实验设计、数据分析和演示。我的全面培训计划将帮助我
实现我的职业目标,成为一名从事临床转化研究的医生科学家。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Grace Conway其他文献
Grace Conway的其他文献
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{{ truncateString('Grace Conway', 18)}}的其他基金
Treatment of Alzheimer’s Disease using Ultrasound-Targeted Microbubble Cavitation-Mediated Blood Brain Barrier Opening to Facilitate Drug Delivery to the Brain
使用超声靶向微泡空化介导的血脑屏障打开促进药物输送至大脑来治疗阿尔茨海默病
- 批准号:
10462037 - 财政年份:2022
- 资助金额:
$ 5.27万 - 项目类别:
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