Endothelial-to-mesenchyma transition and atherosclerosis

内皮间质转化和动脉粥样硬化

基本信息

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
项目类别：
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

项目摘要

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中起重要作用功能。我们和其他实验室的最新研究已经确定了这种连续的内皮成纤维细胞生长因子（FGF）信号传导输入对于维护至关重要血管完整性，渗透性和细胞命运。损失的一个特别重要的结果 FGF输入的是内皮到间质转变（ENDMT）的发展代表从内皮到间充质的命运过渡（平滑肌细胞（SMC），成纤维细胞）表型。由慢性炎症和其他知识较低的刺激引起的诱导， EndMT导致形成新的，由不同的细胞类型组合组成， SMC，成纤维细胞和各种炎症细胞以及细胞外的重塑矩阵（ECM）。我们已经观察到患者的动脉粥样硬化冠状动脉和在小鼠动脉粥样硬化。这些数据表明，EndMT可能会为与慢性炎症有关的疾病进展，例如动脉粥样硬化，和移植动脉疾病。如果正确的话，这一假设将开辟一种可能性的可能性改变这些疾病的自然史，并具有相当大的临床影响。为此，我们旨在测试抑制EndMT是否会抑制会抑制启动，动脉粥样硬化病变的进展和回归，并揭示信号传导和基因连接EndMT，ECM重塑和炎症的表达途径这些影响。