Perivascular fibroblasts, vascular fibrosis, and their contributions to cerebral amyloid angiopathy
血管周围成纤维细胞、血管纤维化及其对脑淀粉样血管病的影响
基本信息
- 批准号:10577536
- 负责人:
- 金额:$ 233.32万
- 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:2022-09-19 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAbeta synthesisAffectAgeAlzheimer&aposs DiseaseAlzheimer&aposs disease therapyAmyloid beta-ProteinAstrocytesAutopsyBiomedical EngineeringBlood VesselsBrainCellsCerebral Amyloid AngiopathyCerebral hemisphere hemorrhageCerebrovascular CirculationCerebrovascular systemCerebrumConnective Tissue CellsCryopreservationDataDementiaDepositionDevelopmentDiseaseEtiologyExhibitsExtracellular MatrixFibroblastsFibrosisFunctional disorderGene SilencingGoalsHemorrhageHistologyHumanImageImaging TechniquesImpaired cognitionIn VitroInjectionsIntracranial HemorrhagesInvestigationJUN geneLinkLiteratureMediatingModelingMolecularMusMyofibroblastOutcomeOutcome MeasurePathologyPathway interactionsPatientsPeripheralPhenotypePhosphatidylinositolsPhosphotransferasesPreclinical Drug DevelopmentPrincipal InvestigatorProcessProductionResearchRisk FactorsRoleSeedsSenile PlaquesShapesSignal PathwaySignal TransductionTGFB1 geneTechniquesTherapeutic InterventionTissue SampleTissue imagingTissuesTransforming Growth Factor betaTransforming Growth Factor beta ReceptorsTransgenic MiceUp-RegulationViralWild Type MouseWorkabeta accumulationabeta depositionarteriolebasebeta amyloid pathologyblood flow measurementbody systembrain parenchymabrain tissuecell typecerebral arterycerebrovascularcombatdefined contributiondruggable targeteffective therapyexperimental studyhuman diseasehuman modelhuman tissuein vitro Modelin vivoin vivo Modelinsightknock-downmouse modelneurovascularnovelpreventprogramsresponsesingle-cell RNA sequencingsmall moleculesmall molecule inhibitortherapeutic targettherapeutically effectivetransgene expressiontreatment strategy
项目摘要
Project summary
Cerebral amyloid angiopathy (CAA) is a disease that occurs when amyloid beta (Aβ) forms deposits on brain
blood vessels. CAA frequently co-occurs with Alzheimer’s disease (AD) and is a significant risk factor for
intracranial hemorrhage and dementia. There are no approved treatments for CAA, and the molecular etiology
of the disease remains unclear, which has prevented the development of effective therapeutic interventions.
Here, we propose to study cerebral perivascular fibroblasts and vascular fibrosis signaling pathways as potential
contributors to CAA pathology. More than 20 years ago, pioneering work showed that astrocyte-specific
upregulation of transforming growth factor beta 1 (TGFβ1), a master regulator of tissue fibrosis, could specifically
induce Aβ pathology in the cerebrovasculature that was reminiscent of CAA. However, the mechanistic actions
of TGFβ1 that could drive such a response were never elucidated. In studying postmortem human brain tissue
from CAA patients, we have found that cerebral perivascular fibroblasts acquire myofibroblast markers around
vessels with Aβ deposition and fibrotic signatures—this phenotype is observed specifically in CAA but not AD or
age-matched controls. Further, this phenotype is replicated in 5xFAD mice after intracerebroventricular injections
of human vascular-derived human Aβ seeds, which yields CAA-like pathology. Hence, we hypothesize that
activation of perivascular fibroblasts and fibrotic signaling pathways in the perivascular niche leads to Aβ
deposition, vascular fibrosis, and acquisition of the CAA phenotype. In Aim 1, we will explore this hypothesis
within two complementary mouse models using three-dimensional tissue imaging techniques, single-cell RNA
sequencing, and blood flow measurements. In Aim 2, we will leverage a novel bioengineered model of human
cerebral arterioles to understand how TGFβ1 shapes the fibrotic microenvironment through multicellular
crosstalk. In Aim 3, again in mouse models, we will target cerebral perivascular fibroblasts and fibrotic signaling
pathways using gene silencing techniques and small molecule treatments and determine if CAA pathology is
lessened. Collectively, these studies will unveil and characterize how perivascular fibroblasts and vascular
fibrosis contribute to CAA pathology. Moreover, these investigations will identify potential preclinical drug
development strategies focused on targeting fibroblast activation and signaling pathways that contribute to a pro-
fibrotic microenvironment in CAA.
项目概要
脑淀粉样血管病 (CAA) 是一种当淀粉样蛋白 β (Aβ) 在大脑中形成沉积物时发生的疾病
血管。 CAA 经常与阿尔茨海默病 (AD) 同时发生,并且是阿尔茨海默病的一个重要危险因素
颅内出血和痴呆。 CAA 尚无批准的治疗方法,其分子病因学
该疾病的病因尚不清楚,这阻碍了有效治疗干预措施的发展。
在这里,我们建议研究脑血管周围成纤维细胞和血管纤维化信号通路的潜在作用
CAA 病理学的贡献者。 20多年前,开创性工作表明星形胶质细胞特异性
组织纤维化的主要调节因子——转化生长因子β1(TGFβ1)的上调可以特异性地
在脑血管系统中诱导 Aβ 病理,这让人想起 CAA。然而,机械动作
TGFβ1 能够驱动这种反应的机制从未被阐明。研究死后人类脑组织
从 CAA 患者中,我们发现脑血管周围成纤维细胞获得周围肌成纤维细胞标志物
具有 Aβ 沉积和纤维化特征的血管——这种表型特别是在 CAA 中观察到,但在 AD 或
年龄匹配的控制。此外,这种表型在脑室内注射后在 5xFAD 小鼠中复制
人类血管来源的人类 Aβ 种子,产生类似 CAA 的病理学。因此,我们假设
血管周围成纤维细胞的激活和血管周围微环境中的纤维化信号通路导致 Aβ
沉积、血管纤维化和 CAA 表型的获得。在目标 1 中,我们将探讨这个假设
在使用三维组织成像技术的两个互补小鼠模型中,单细胞RNA
测序和血流测量。在目标 2 中,我们将利用一种新颖的人类生物工程模型
脑动脉以了解 TGFβ1 如何通过多细胞塑造纤维化微环境
相声。在目标 3 中,同样是在小鼠模型中,我们将针对大脑血管周围成纤维细胞和纤维化信号传导
使用基因沉默技术和小分子治疗的途径,并确定 CAA 病理学是否是
减少了。总的来说,这些研究将揭示并描述血管周围成纤维细胞和血管如何
纤维化导致 CAA 病理。此外,这些研究将确定潜在的临床前药物
开发策略侧重于针对成纤维细胞激活和信号通路,有助于促进
CAA 中的纤维化微环境。
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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Ethan Lippmann其他文献
Ethan Lippmann的其他文献
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{{ truncateString('Ethan Lippmann', 18)}}的其他基金
STAT3 activation in astrocytes as a driver of neurovascular dysfunction in Alzheimer's disease and related dementias
星形胶质细胞中 STAT3 的激活是阿尔茨海默病和相关痴呆症神经血管功能障碍的驱动因素
- 批准号:
10562131 - 财政年份:2022
- 资助金额:
$ 233.32万 - 项目类别:
STAT3 activation in astrocytes as a driver of neurovascular dysfunction in Alzheimer's disease and related dementias
星形胶质细胞中 STAT3 的激活是阿尔茨海默病和相关痴呆症神经血管功能障碍的驱动因素
- 批准号:
10785691 - 财政年份:2022
- 资助金额:
$ 233.32万 - 项目类别:
iPSC-derived neurovascular tissue model of cerebral amyloiad angiopathy
iPSC 衍生的脑淀粉样血管病神经血管组织模型
- 批准号:
10044329 - 财政年份:2020
- 资助金额:
$ 233.32万 - 项目类别:
Modeling spinal cord axis patterning with human pluripotent stem cells
用人类多能干细胞模拟脊髓轴模式
- 批准号:
8644522 - 财政年份:2013
- 资助金额:
$ 233.32万 - 项目类别:
Modeling spinal cord axis patterning with human pluripotent stem cells
用人类多能干细胞模拟脊髓轴模式
- 批准号:
8852002 - 财政年份:2013
- 资助金额:
$ 233.32万 - 项目类别:














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