The effects of amyloid beta on pericyte remodeling and brain capillary function in vivo
β淀粉样蛋白对体内周细胞重塑和脑毛细血管功能的影响
基本信息
- 批准号:9898221
- 负责人:
- 金额:$ 23.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-04-01 至 2022-01-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAddressAdultAffectAgeAgingAlzheimer&aposs DiseaseAmyloidAmyloid beta-ProteinAmyloid depositionBasic ScienceBiologyBloodBlood - brain barrier anatomyBlood CellsBlood VesselsBlood capillariesBlood flowBrainCaliberCellsCerebral Amyloid AngiopathyCerebrovascular CirculationCerebrovascular DisordersCessation of lifeCommunicationCrossbreedingDataDefectDepositionDevelopmentDisease ProgressionEndothelial CellsEndotheliumExhibitsFutureHealthHumanImageImpairmentInjuryKnowledgeLabelLeadLightMaintenanceMeasuresMicroscopyMicrovascular DysfunctionMusNerve DegenerationOpticsOxygenPartial PressurePathologyPericytesPhysiologicalProcessResolutionRoleShapesSpecificityStretchingStructureSurfaceTestingTheftTimeTissuesUnited StatesVascular DementiaVascular SystemVascular blood supplyVisualizationabeta depositionage effectagedblood-brain barrier permeabilizationbrain remodelingcapillary bedcell typecerebral capillarydesignexperimental groupin vivoin vivo imagingin vivo optical imaginginsightmiddle agemouse modelnervous system disordernovelnovel strategiespre-clinicalpreservationrepairedresponsesocioeconomicstherapeutic developmenttherapeutic targettissue oxygenationtooltwo photon microscopytwo-photonyoung adult
项目摘要
Project Summary
Brain capillaries are composed of a single layer of endothelial cells covered by specialized mural cells called
pericytes. Communication between pericytes and endothelial cells is essential for brain capillary health. Recent
studies indicate that Alzheimer’s disease and vascular dementia involve increased death or degeneration of
brain pericytes. This is thought to contribute to the impairment of both blood-brain barrier integrity and cerebral
blood flow, which subsequently exacerbates neurodegeneration. Therefore, strategies to mitigate or
compensate for loss of pericyte coverage may help to preserved vascular function in these neurological
diseases. We recently discovered that brain pericytes have the ability to structurally remodel in the adult brain.
In response to focal ablation of single pericytes in vivo, we observed the robust extension of processes from
neighboring pericytes, which could reach over large stretches of capillary bed to regain contact with the
exposed endothelium. In young healthy mice, the transient loss of pericyte coverage led to persistent capillary
dilation and abnormally high blood cell flux, until pericyte contact was regained. These findings suggest that
pericyte remodeling is a reparative mechanism to compensate for pericyte loss. We hypothesize that this
capacity is diminished with age and further impaired with amyloid deposition during cerebral amyloid
angiopathy, a frequent small vessel disease in Alzheimer’s. To address this hypothesis, we plan to use in vivo
two-photon microscopy to directly observe pericytes dynamics in normal mice and mice with cerebral amyloid
angiopathy. In Aim 1, we will test whether remodeling capacity is reduced in young and aged Tg-SwDI mice,
which exhibit a unique enrichment of capillary amyloid deposits over time. In Aim 2, we will use a novel
oxygen-sensitive probe designed for two-photon imaging to better understand the consequence of pericyte
loss on blood flow and local tissue oxygenation. This project will shed light on a largely unstudied facet of
pericyte biology that may lead to novel approaches to augment pericyte-endothelial contact and preserve brain
capillary health in Alzheimer’s disease. It will advance the field by: 1) Characterizing the dynamics of pericyte
remodeling in detail using in vivo optical imaging, 2) providing insight on how small vessel disease impairs the
reparative capacity of brain capillaries, and 3) promoting the development of new tools to study pericytes with
unprecedented specificity in the living mouse brain.
项目摘要
脑毛细血管由单层内皮细胞组成,其上覆盖着专门的壁细胞,
周细胞周细胞和内皮细胞之间的通信对于脑毛细血管健康是必不可少的。最近
研究表明,阿尔茨海默病和血管性痴呆涉及增加的死亡或退化,
脑周细胞这被认为是导致血脑屏障完整性和脑损伤的原因。
血液流动,这随后加剧了神经变性。因此,减轻或
补偿周细胞覆盖的损失可能有助于保护这些神经系统中的血管功能,
疾病我们最近发现,大脑周细胞具有在成人大脑中进行结构重塑的能力。
为了响应体内单个周细胞的局灶性消融,我们观察到了从
邻近的周细胞,它可以到达大面积的毛细血管床,以重新与毛细血管接触。
暴露的内皮细胞。在年轻的健康小鼠中,周细胞覆盖的短暂丧失导致持续的毛细血管
扩张和异常高的血细胞流量,直到周细胞接触恢复。这些发现表明
周细胞重塑是补偿周细胞损失的修复机制。我们假设这
随着年龄的增长,容量减少,并且在脑淀粉样蛋白形成过程中随着淀粉样蛋白沉积而进一步受损。
血管病,阿尔茨海默氏症中常见的小血管疾病。为了解决这一假设,我们计划在体内使用
双光子显微镜直接观察正常小鼠和脑淀粉样蛋白小鼠的周细胞动力学
血管病在目标1中,我们将测试年轻和老年Tg-SwDI小鼠的重塑能力是否降低,
其随着时间的推移表现出毛细血管淀粉样蛋白沉积物的独特富集。在目标2中,我们将使用一本小说
设计用于双光子成像的氧敏探针,以更好地了解周细胞
血流和局部组织氧合的损失。这个项目将揭示一个基本上未研究的方面,
周细胞生物学可能导致新的方法来增加周细胞-内皮细胞接触和保护脑
老年痴呆症中的毛细血管健康它将推进该领域的工作:1)表征周细胞的动力学
使用体内光学成像详细重塑,2)提供关于小血管疾病如何损害
脑毛细血管的修复能力,3)促进研究周细胞的新工具的发展,
前所未有的特异性。
项目成果
期刊论文数量(1)
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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Andy Y Shih其他文献
Andy Y Shih的其他文献
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{{ truncateString('Andy Y Shih', 18)}}的其他基金
In vivo two-photon imaging of vascular invasion and stem cell translocation in calvarial bone
颅骨血管侵袭和干细胞易位的体内双光子成像
- 批准号:
10603163 - 财政年份:2023
- 资助金额:
$ 23.25万 - 项目类别:
Pericyte control of capillary perfusion in the Alzheimer's disease brain
阿尔茨海默病大脑中毛细血管灌注的周细胞控制
- 批准号:
10655813 - 财政年份:2023
- 资助金额:
$ 23.25万 - 项目类别:
Brain Drain: In Vivo Optical Interrogation of Venular Function in Gray and White Matter
脑流失:灰质和白质中小静脉功能的体内光学询问
- 批准号:
10463455 - 财政年份:2022
- 资助金额:
$ 23.25万 - 项目类别:
Pericyte structural plasticity and cerebrovascular health
周细胞结构可塑性与脑血管健康
- 批准号:
10374139 - 财政年份:2020
- 资助金额:
$ 23.25万 - 项目类别:
Pericyte structural plasticity and cerebrovascular health
周细胞结构可塑性与脑血管健康
- 批准号:
10163765 - 财政年份:2020
- 资助金额:
$ 23.25万 - 项目类别:
Pericyte structural plasticity and cerebrovascular health
周细胞结构可塑性与脑血管健康
- 批准号:
9894994 - 财政年份:2020
- 资助金额:
$ 23.25万 - 项目类别:
Pericyte structural plasticity and cerebrovascular health
周细胞结构可塑性与脑血管健康
- 批准号:
10576299 - 财政年份:2020
- 资助金额:
$ 23.25万 - 项目类别:
Pericyte structural plasticity and cerebrovascular health
周细胞结构可塑性与脑血管健康
- 批准号:
10783214 - 财政年份:2020
- 资助金额:
$ 23.25万 - 项目类别:
Optical Interrogation of Venular Function in Cerebral Gray and White Matter
大脑灰质和白质中静脉功能的光学询问
- 批准号:
10221601 - 财政年份:2020
- 资助金额:
$ 23.25万 - 项目类别:
Diversity Supplement: Pericyte structural plasticity and cerebrovascular health
多样性补充:周细胞结构可塑性与脑血管健康
- 批准号:
10605744 - 财政年份:2020
- 资助金额:
$ 23.25万 - 项目类别:
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