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

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.
项目摘要 脑淀粉样血管病(Cerebral amyloid angiopathy,CAA)是指β淀粉样蛋白(amyloid beta,Aβ)在脑组织中沉积形成的一种疾病 血管CAA经常与阿尔茨海默病(AD)共同发生,并且是阿尔茨海默病(AD)的重要风险因素。 颅内出血和痴呆目前还没有批准的CAA治疗方法, 这种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作为潜在的 CAA病理学的贡献者。20多年前,开创性的工作表明, 组织纤维化的主要调节因子转化生长因子β 1(TGFβ1)的上调, 在血管系统中诱导Aβ病理学,使人联想到CAA。然而,机械的行动 TGFβ1可以驱动这样的反应从未阐明。在研究死后的人脑组织时 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-这种表型在CAA中特异性观察到,但在AD或 年龄匹配的对照组。此外,这种表型在脑室内注射后在5xFAD小鼠中复制 人血管来源的人Aβ种子,产生CAA样病理。因此,我们假设, 血管周围成纤维细胞和血管周围小生境中纤维化信号通路的激活导致Aβ 沉积、血管纤维化和CAA表型的获得。在目标1中,我们将探讨这一假设 在使用三维组织成像技术的两个互补小鼠模型中, 测序和血流测量。在目标2中,我们将利用一种新的人类生物工程模型, 大脑小动脉了解TGFβ1如何通过多细胞 串话。在目标3中,同样在小鼠模型中,我们将靶向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来确定CAA病理是否是 减少。总的来说,这些研究将揭示和表征血管周围成纤维细胞和血管 纤维化有助于CAA病理学。此外,这些研究将确定潜在的临床前药物 发展战略的重点是针对成纤维细胞活化和信号通路,有助于促进 CAA纤维化微环境

项目成果

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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 Organoids
iPSC 衍生的神经血管类器官
  • 批准号:
    10373981
  • 财政年份:
    2020
  • 资助金额:
    $ 233.32万
  • 项目类别:
iPSC-derived Neurovascular Organoids
iPSC 衍生的神经血管类器官
  • 批准号:
    10599940
  • 财政年份:
    2020
  • 资助金额:
    $ 233.32万
  • 项目类别:
iPSC-derived Neurovascular Organoids
iPSC 衍生的神经血管类器官
  • 批准号:
    10775461
  • 财政年份:
    2020
  • 资助金额:
    $ 233.32万
  • 项目类别:
iPSC-derived Neurovascular Organoids
iPSC 衍生的神经血管类器官
  • 批准号:
    10683029
  • 财政年份:
    2020
  • 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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