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：
Ethan Lippmann
金额：
$ 233.32万
依托单位：
VANDERBILT UNIVERSITY
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：
https://reporter.nih.gov/project-details/10577536
关键词：
3-Dimensional Abeta synthesis Affect Age Alzheimer&apos s Disease Alzheimer&apos 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

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（CAA）是一种淀粉样蛋白β（Aβ）在大脑上形成沉积物时发生的疾病血管。 CAA经常与阿尔茨海默氏病（AD）同时发生，并且是重要的风险因素颅内出血和痴呆。没有批准的CAA治疗方法和分子病因该疾病尚不清楚，这阻止了有效的治疗干预措施的发展。在这里，我们建议研究脑周围血管成纤维细胞和血管纤维化信号通路 CAA病理学的贡献者。 20多年前，开创性的工作表明，星形胶质细胞特定于组织纤维化的主要调节剂转化生长因子β1（TGFβ1）的上调可以具体在脑血管造期间诱导Aβ病理，使人联想起CAA。但是，机械行动从未阐明可以驱动这种反应的TGFβ1的TGFβ1。在研究死后人脑组织从CAA患者那里，我们发现脑周围成纤维细胞在周围获得肌纤维细胞标记具有Aβ沉积和纤维化特征的血管 - 该表型在CAA中特别观察到，但未在AD中观察到年龄匹配的控件。此外，该表型在脑室注射后在5xFAD小鼠中复制人类血管衍生的人Aβ种子，产生类似CAA的病理。因此，我们假设血管周围成纤维细胞的激活和血管周期菌群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AIM 1中，我们将探讨这个假设在两个完整的小鼠模型中，使用三维组织成像技术，单细胞RNA 测序和血流测量值。在AIM 2中，我们将利用人类的新型生物工程模型脑小动脉以了解TGFβ1如何通过多细胞形成纤维化微环境相声。在AIM 3中，在鼠标模型中，我们将靶向脑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处理的途径，并确定CAA病理是否为减少。总的来说，这些研究将揭露并表征周围的成纤维细胞和血管纤维化有助于CAA病理。此外，这些调查将确定潜在的临床前药物开发策略的重点是靶向有助于促进的成纤维细胞激活和信号传导途径 CAA中的纤维化微环境。