Molecular mechanisms of extracellular vesicle-derived modulation of transcytosis at the blood brain barrier
细胞外囊泡衍生的血脑屏障转胞吞调节的分子机制
基本信息
- 批准号:10039319
- 负责人:
- 金额:$ 45.51万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-17 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:AstrocytesBlood - brain barrier anatomyBlood CirculationBlood VesselsBrainBrain DiseasesBreast Cancer Early DetectionBreast Cancer PatientCell CommunicationCellsClinicalDevelopmentDiagnosticDiseaseDistantDropsDrug Delivery SystemsEarly DiagnosisEarly identificationEndocytosis PathwayEndothelial CellsEndotheliumFoundationsFutureGenetic MaterialsHome environmentImmuneIn VitroMalignant NeoplasmsMediatingMetastatic malignant neoplasm to brainMolecularNatureNeoplasm MetastasisNeurodegenerative DisordersNucleic AcidsOrganPathologicPathologyPathway interactionsPatientsPericytesPhysiologicalPlayPreparationProcessProteinsRoleStructureSurvival RateTestingTherapeuticTimeTissuesTravelTumor-DerivedVesicleWomanbasebrain endothelial cellcell typeclinically relevantdesignearly detection biomarkersextracellular vesiclesfootin vivo Modelinnovationinsightintercellular communicationmalignant breast neoplasmnanoscaleneoplastic cellnovelnovel diagnosticsnovel therapeuticsoutcome forecastpassive transportstem cellstranscytosisvesicular release
项目摘要
Project Summary/Abstract
Extracellular vesicles (EVs) are nanoscale vesicles containing a variety of proteins and nucleic acids that
can be transferred to other cells. It is widely accepted that EVs released from a variety of cells into the
circulation can home to different organs for distant intercellular communication. For instance, circulating tumor-
derived EVs can contribute to metastasis formation through preparing a niche at pre-metastatic organs.
However, the mechanisms by which circulating EVs interact with the different endothelial barriers to penetrate
into distant organs remain poorly understood. Elucidating these mechanisms will provide novel insights into the
currently unknown mechanisms of intercellular EV processing in endothelial barriers, which can then be
generalized to a variety of other barriers, leading to broad clinical and scientific implications. This proposal
aims to elucidate the molecular mechanisms by which circulating EVs interact with the unique vascular
structure of the brain, the blood-brain barrier (BBB), within the context of breast cancer brain metastasis.
Breast cancer is the most common cause of brain metastasis in women and is associated with a median
survival time of only 10 months. Development of efficient diagnostics and therapeutics for brain metastasis has
been hindered in part by the restrictive nature of the BBB. We have recently demonstrated that tumor-derived
EVs can breach the BBB and have identified “transcytosis” as the mechanism underlying this process.
Importantly, we have also demonstrated that through modulating the endocytic pathway in endothelial cells,
tumor-derived EVs can circumvent the low rates of transcytosis at the BBB and facilitate their transcellular
transport. This finding suggests a novel mechanism underlying the interaction of circulating EVs and the brain
endothelium. In this proposal, we will identify the molecular mechanism(s) underlying EV-derived modulation of
transcytosis and the clinical implications of these mechanisms for development of early diagnostics for brain
metastasis. These studies will be pursued within the context of the following Specific Aims:
1. To determine the mechanism(s) by which breast cancer-derived EVs modulate the endocytic pathway
in brain endothelial cells
2. To identify the EV cargoes that promote facilitation of transcytosis in brain endothelial cells
3. To determine the correlation between EV content and breast cancer brain metastasis
Our proposed studies will identify novel mechanisms that mediate the interaction of circulating EVs with brain
endothelial cells and in doing so, can unmask early steps in the process of brain metastasis formation and
provide the foundation upon which to develop novel diagnostic approaches for early detection of brain
metastasis.
项目摘要/摘要
细胞外小泡(EV)是含有多种蛋白质和核酸的纳米级小泡
可以转移到其他细胞。人们普遍认为,电动汽车从各种细胞释放到
血液循环可以到达不同的器官,进行远距离的细胞间通讯。例如,循环肿瘤-
衍生的EVS可以通过在转移前的器官上准备一个利基来促进转移的形成。
然而,循环EV与不同的内皮屏障相互作用以穿透的机制
进入遥远的器官仍然知之甚少。阐明这些机制将为我们提供对
目前尚不清楚EV在内皮屏障中的细胞间处理机制,然后可以
推广到各种其他障碍,导致广泛的临床和科学意义。这项建议
旨在阐明循环中的EV与独特的血管相互作用的分子机制
脑的结构,血脑屏障(BBB),在乳腺癌脑转移的背景下。
乳腺癌是女性脑转移最常见的原因,与中位数
存活时间只有10个月。脑转移瘤的有效诊断和治疗方法的发展
在一定程度上受到了BBB的限制性的阻碍。我们最近证明了肿瘤来源的
EVS可以破坏血脑屏障,并已确定“跨细胞作用”是这一过程的基础机制。
重要的是,我们还证明了通过调节内皮细胞的内吞途径,
肿瘤来源的EV可以绕过血脑屏障的低穿细胞率,并促进其跨细胞
运输。这一发现表明了一种新的机制,即循环中的EVS与大脑相互作用
内皮细胞。在这项建议中,我们将确定EV来源的调制的分子机制(S)。
细胞转运及其对发展脑早期诊断的临床意义
转移。这些研究将在下列具体目标的范围内进行:
1.确定乳腺癌来源的EV调节细胞内吞途径的机制(S)
在脑内皮细胞中
2.鉴定促进脑血管内皮细胞易化的EV载体
3.探讨EV含量与乳腺癌脑转移的关系
我们提出的研究将确定调节循环中的电动汽车与大脑相互作用的新机制。
通过这样做,可以揭示脑转移形成过程中的早期步骤,并
为开发新的脑早期检测诊断方法奠定了基础
转移。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The role of extracellular vesicles in the physiological and pathological regulation of the blood-brain barrier.
- DOI:10.1096/fba.2021-00045
- 发表时间:2021-09
- 期刊:
- 影响因子:2.7
- 作者:Busatto S;Morad G;Guo P;Moses MA
- 通讯作者:Moses MA
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{{ truncateString('MARSHA A MOSES', 18)}}的其他基金
(PQA2): Escape from breast tumor dormancy: convergence of obesity and menopause
(PQA2):逃离乳腺肿瘤休眠:肥胖与更年期的融合
- 批准号:
8848797 - 财政年份:2014
- 资助金额:
$ 45.51万 - 项目类别:
(PQA2): Escape from breast tumor dormancy: convergence of obesity and menopause
(PQA2):逃离乳腺肿瘤休眠:肥胖与更年期的融合
- 批准号:
8687053 - 财政年份:2014
- 资助金额:
$ 45.51万 - 项目类别:
(PQA2): Escape from breast tumor dormancy: convergence of obesity and menopause
(PQA2):逃离乳腺肿瘤休眠:肥胖与更年期的融合
- 批准号:
9248212 - 财政年份:2014
- 资助金额:
$ 45.51万 - 项目类别: