Endothelial-to-mesenchyma transition and atherosclerosis

内皮间质转化和动脉粥样硬化

• 批准号: 9219801
• 负责人: Martin A Schwartz
• 金额: $ 82.77万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-12 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9219801
• 关键词: Apolipoprotein E; Arterial Disorder; Arterial Fatty Streak; Atherosclerosis; Blood Vessels; Cells; Chemicals; Chronic; Clinical; Coronary; Coronary artery; Data; Deposition; Development; Disease; Disease Progression; Event; Extracellular Matrix; FGFR1 gene; Feedback; Fibroblast Growth Factor; Fibroblasts; Fibronectins; Gene Expression; Genetic; Genetically Engineered Mouse; Growth; Homeostasis; Human; Inflammation; Inflammation Mediators; Inflammatory; Interferon-alpha; Interleukin-1 beta; Laboratories; Link; Maintenance; Mediating; Mesenchymal; Mesenchyme; MicroRNAs; Molecular; Molecular Biology; Molecular Target; Mus; Myocardial Infarction; Natural History; Organ; Pathway interactions; Patients; Peripheral Vascular Diseases; Permeability; Phenotype; Play; Process; Progressive Disease; Reporting; Role; Severities; Signal Transduction; Small Interfering RNA; Smooth Muscle Myocytes; Specimen; Stimulus; Stroke; TNF gene; Techniques; Testing; Therapeutic; Transforming Growth Factor beta; Transplantation; base; cell type; disease natural history; driving force; genetic approach; mouse model; nanoparticle; neointima formation; novel; novel therapeutic intervention; novel therapeutics; pre-clinical; shear stress

Project Summary Vascular homeostasis plays an important role in maintenance of normal vessel and organ function. Recent studies from our and other laboratories have established that continuous endothelial fibroblast growth factor (FGF) signaling input is critical for the maintenance of vascular integrity, permeability and cell fate. One particularly important consequence of the loss of FGF input is the development of endothelial-to-mesenchymal transition (EndMT) that represents a fate transition from endothelial to a mesenchymal-like (smooth muscle cell (SMC), fibroblast) phenotype. Induced by chronic inflammation and other poorly understood stimuli, EndMT leads to formation of neointima that consists of a combination of different cell types, SMCs, fibroblasts and various inflammatory cells as well as remodeling of the extracellular matrix (ECM). We have observed extensive EndMT in atherosclerotic coronary arteries in patients and in mouse atherosclerosis. These data suggest that EndMT may make a major contribution to disease progression in illnesses associated with chronic inflammation, such as atherosclerosis, and transplant arteriopathy. If correct, this hypothesis would open a possibility to fundamentally change the natural history of these illnesses with considerable clinical impact. To this end, we aim to test whether suppression of EndMT will inhibit will inhibit initiation, progression and regression of atherosclerotic lesions, and to unravel the signaling and gene expression pathways that connect EndMT, ECM remodeling and inflammation that mediate these effects.

项目摘要 血管稳态在维持正常血管和器官功能中起着重要作用 功能我们和其他实验室最近的研究表明， 内皮成纤维细胞生长因子（FGF）信号输入对于维持 血管完整性、渗透性和细胞命运。损失的一个特别重要的后果是 FGF输入的最重要的原因是内皮细胞向间充质细胞转化（EndMT）的发展， 代表从内皮细胞到间充质样细胞（平滑肌细胞（SMC）， 成纤维细胞）表型。由慢性炎症和其他尚不清楚的刺激引起， EndMT导致新生内膜的形成，新生内膜由不同细胞类型的组合组成， 平滑肌细胞、成纤维细胞和各种炎症细胞以及细胞外基质的重塑 矩阵（ECM）。 我们已经观察到广泛的EndMT在动脉粥样硬化患者的冠状动脉， 小鼠动脉粥样硬化这些数据表明，EndMT可能对 在与慢性炎症，如动脉粥样硬化， 和移植动脉病如果是正确的，这一假设将从根本上打开一个可能性， 改变这些疾病的自然史，具有相当大的临床影响。 为此，我们的目标是测试EndMT的抑制是否会抑制起始， 动脉粥样硬化病变的进展和消退，并解开信号和基因 连接EndMT、ECM重塑和炎症的表达途径， 这些影响。