Mechanisms of vasomotion-mediated perivascular clearance in cerebral amyloid angiopathy
脑淀粉样血管病血管舒缩介导的血管周围清除机制
基本信息
- 批准号:10518909
- 负责人:
- 金额:$ 61.51万
- 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:2022-08-01 至 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:Abeta clearanceAffectAgeAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease diagnosisAmyloid beta-ProteinArteriesAutomobile DrivingBlood VesselsBlood capillariesBrainCalciumCell physiologyCellsCephalicCerebral Amyloid AngiopathyCerebral hemisphere hemorrhageCerebrospinal FluidCerebrovascular systemChronicCoupledCouplingDataDementiaDepositionDextransDiseaseDisease modelDrainage procedureEarly InterventionElderlyEventFrequenciesFunctional Magnetic Resonance ImagingFunctional disorderFutureGenesHemorrhageHigh PrevalenceHumanImageImaging TechniquesImmunotherapyImpaired cognitionImpairmentIndividualInjectionsIntercellular FluidInterventionLabelLeadLiteratureLobarMeasuresMediatingMetabolicMethodsModelingMusNutrientOxygenPathway interactionsPatientsPatternPhotic StimulationPhysiologic pulsePhysiologicalPhysiologyPlayProcessPropertyResearchResolutionRestRiskRoleSeveritiesSmooth Muscle MyocytesSpeedSystemTechniquesTestingTimeTracerTransgenic MiceTranslationsVascular DiseasesVascular Smooth MuscleVisualWaste ProductsWorkabeta accumulationabeta depositionaging brainarterioleawakebaseblood oxygen level dependentbrain dysfunctionbrain healthbrain tissuecerebrospinal fluid flowclinical diagnosisdesigndriving forceeffective therapyexperimental studyfluid flowhemodynamicsimprovedin vivoin vivo optical imaginginnovationmouse modelneuroimagingnew therapeutic targetnon-invasive imagingnoveloptical imagingoptogeneticsparticlepreservationpreventsingle-cell RNA sequencingsolutetherapeutic developmenttranscriptomicstranslational approachtwo photon microscopyvasomotionwasting
项目摘要
Project Summary / Abstract
Title project: “Mechanisms of vasomotion-mediated perivascular clearance in cerebral amyloid angiopathy”
The blood vessels in the brain play an important role in facilitating clearance of metabolic waste products.
Impaired perivascular clearance of amyloid β (Aβ) has been implicated in the pathophysiology of cerebral
amyloid angiopathy (CAA) and Alzheimer’s disease. However, fundamental unknows including the
directionality and major driving forces of perivascular clearance remain, which has hampered the development
of therapeutic strategies aimed at targeting the perivascular waste clearance system. Moreover, experimental
observations in mice have remain largely unexplored in the human brain. Prior work from the applicant
uncovered a role for vasomotion – slow spontaneous oscillations of arterioles generated by vascular smooth
muscle cells (SMCs) – as a major driving force for perivascular clearance. This project will further zoom in on
vasomotion and test the novel hypothesis that targeting vascular SMCs may provide an attractive approach to
enhance vasomotion and thereby facilitate perivascular Aβ clearance. This project will use CAA as a model
disease to test this hypothesis, as CAA is characterized by the gradual deposition of vascular Aβ, impaired
perivascular clearance, SMC degeneration, and vascular dysfunction. The aims of this project are to further
unravel the physiological basis of vasomotion-mediated perivascular clearance, to determine the effect of
vascular Aβ accumulation on vasomotion and clearance, to explore the potential of enhancing low frequency
arteriolar oscillations as an intervention strategy to successfully clear Aβ from the brain, and to measure the
coupling between low frequency hemodynamics and fluid flow in the human brain. We will use a translational
approach, utilizing optical imaging techniques in awake mice coupled with direct optogenetic stimulation of
vascular SMCs, as well as fast functional MRI in human individuals with and without CAA. Successful
completion of these aims will improve our understanding of the physiological basis of vasomotion-mediated
perivascular clearance and provide much needed proof-of-concept data to support the potential of modulating
low frequency arteriolar oscillations as an early intervention strategy to promote Aβ clearance from the brain.
项目总结/摘要
标题项目:“脑淀粉样血管病中血管运动介导的血管周围清除机制”
大脑中的血管在促进代谢废物的清除方面起着重要作用。
β淀粉样蛋白(Aβ)血管周围清除障碍与脑缺血的病理生理学有关。
淀粉样血管病(CAA)和阿尔茨海默病。然而,基本的未知数,包括
血管周围清除的方向性和主要驱动力仍然存在,这阻碍了发展
针对血管周围废物清除系统的治疗策略。此外,实验
在小鼠中的观察结果在人脑中仍然基本上未被探索。申请人之前的工作
揭示了血管运动的作用-血管平滑肌产生的小动脉的缓慢自发振荡
肌肉细胞(SMC)-作为血管周围清除的主要驱动力。该项目将进一步放大
血管舒缩和测试新的假设,靶向血管平滑肌细胞可能提供一个有吸引力的方法,
增强血管舒缩,从而促进血管周围Aβ清除。本项目将使用CAA作为模型
疾病来验证这一假设,因为CAA的特征是血管Aβ逐渐沉积,受损
血管周围清除、SMC变性和血管功能障碍。该项目的目的是进一步
阐明血管舒缩介导的血管周围清除的生理基础,以确定
血管Aβ积聚对血管舒缩和清除的影响,探讨低频增强的潜力
小动脉振荡作为一种干预策略,成功地从大脑中清除Aβ,并测量
低频血液动力学和人脑中的流体流动之间的耦合。我们将使用一个平移
方法,利用清醒小鼠中的光学成像技术,结合直接光遗传刺激,
血管平滑肌细胞,以及快速功能性MRI在人类个体与CAA。成功
这些目标的完成将提高我们对血管舒缩介导的生理基础的理解。
血管周围清除率,并提供急需的概念验证数据,以支持调节
低频小动脉振荡作为早期干预策略,以促进Aβ从脑中清除。
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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Susanne Janneke Van Veluw其他文献
Susanne Janneke Van Veluw的其他文献
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{{ truncateString('Susanne Janneke Van Veluw', 18)}}的其他基金
Perivascular Inflammation and Vascular Remodeling: A Common Cause of Hemorrhage in Cerebral Small Vessel Diseases?
血管周围炎症和血管重塑:脑小血管疾病出血的常见原因?
- 批准号:
10861499 - 财政年份:2023
- 资助金额:
$ 61.51万 - 项目类别:
Mechanisms of Vasomotion-mediated Perivascular Clearance in Cerebral Amyloid Angiopathy
脑淀粉样血管病中血管舒缩介导的血管周围清除机制
- 批准号:
10669786 - 财政年份:2022
- 资助金额:
$ 61.51万 - 项目类别:
Unraveling the mechanisms of microhemorrhages in cerebral amyloid angiopathy
揭示脑淀粉样血管病微出血的机制
- 批准号:
10406382 - 财政年份:2018
- 资助金额:
$ 61.51万 - 项目类别:
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