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

• 批准号: 10577536
• 负责人: Ethan Lippmann
• 金额: $ 233.32万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10577536
• 关键词: 3-Dimensional; Abeta synthesis; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease therapy; Amyloid beta-Protein; Astrocytes; Autopsy; Biomedical Engineering; Blood Vessels; Brain; Cells; Cerebral Amyloid Angiopathy; Cerebral hemisphere hemorrhage; Cerebrovascular Circulation; Cerebrovascular system; Cerebrum; Connective Tissue Cells; Cryopreservation; Data; Dementia; Deposition; Development; Disease; Etiology; Exhibits; Extracellular Matrix; Fibroblasts; Fibrosis; Functional disorder; Gene Silencing; Goals; Hemorrhage; Histology; Human; Image; Imaging Techniques; Impaired cognition; In Vitro; Injections; Intracranial Hemorrhages; Investigation; JUN gene; Link; Literature; Mediating; Modeling; Molecular; Mus; Myofibroblast; Outcome; Outcome Measure; Pathology; Pathway interactions; Patients; Peripheral; Phenotype; Phosphatidylinositols; Phosphotransferases; Preclinical Drug Development; Principal Investigator; Process; Production; Research; Risk Factors; Role; Seeds; Senile Plaques; Shapes; Signal Pathway; Signal Transduction; TGFB1 gene; Techniques; Therapeutic Intervention; Tissue Sample; Tissue imaging; Tissues; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Transgenic Mice; Up-Regulation; Viral; Wild Type Mouse; Work; abeta accumulation; abeta deposition; arteriole; base; beta amyloid pathology; blood flow measurement; body system; brain parenchyma; brain tissue; cell type; cerebral artery; cerebrovascular; combat; defined contribution; druggable target; effective therapy; experimental study; human disease; human model; human tissue; in vitro Model; in vivo; in vivo Model; insight; knock-down; mouse model; neurovascular; novel; prevent; programs; response; single-cell RNA sequencing; small molecule; small molecule inhibitor; therapeutic target; therapeutically effective; transgene expression; treatment strategy

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， 诱导脑血管中的Aβ病理学，这让人想起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途径，并确定CAA病理学是否 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