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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。