Matricellular protein CCN3 in vascular homeostasis

基质细胞蛋白 CCN3 在血管稳态中的作用

基本信息

批准号：
10504077
负责人：
Zhiyong Lin
金额：
$ 67.78万
依托单位：
EMORY 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：
2022-07-15 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10504077
关键词：
Address Angiotensin II Animals Anti-Inflammatory Agents Aorta Aortic Aneurysm Atlases Automobile Driving Behavior Biochemical Blood Vessels Cells Chest Communication Development Dilatation - action Dissection Endothelial Cells Endothelium Environmental Risk Factor Event Exhibits Exposure to Extracellular Matrix Degradation Foundations Functional disorder Gene Family Glean Health Histologic Homeostasis In Vitro Incidence Infiltration Inflammasome Inflammation Infusion procedures Knockout Mice Knowledge Laboratories Lead Left Leukocytes Maintenance Marfan Syndrome Medical Modeling Molecular Morbidity - disease rate Mus Mutation Operative Surgical Procedures Organ Oxidative Stress Pathogenesis Pathologic Pharmacology Physiological Physiology Plant Roots Play Prevention Property Proteins Reactive Oxygen Species Regulation Research Role Rupture Secondary to Severities Signal Pathway Therapeutic Thoracic Aortic Aneurysm Tissues Vascular Diseases Vascular Endothelium Work cell type conditional knockout endothelial dysfunction experimental study gene network in vivo inhibitor insight member mortality mouse model novel novel therapeutic intervention novel therapeutics prevent single-cell RNA sequencing transcriptome sequencing vascular inflammation

项目摘要

SUMMARY Aortic homeostasis is essential for vascular health. The vascular endothelium is a vital organ whose health is essential to normal vascular physiology; when dysregulated, it becomes a critical factor in the pathogenesis of a variety of vascular diseases. Growing evidence indicates that endothelial cells (ECs) play an underappreciated role in the development and progression of thoracic aortic aneurysm and dissection (TAAD). Most notably, compromised barrier integrity has been implicated as a precursor to the development of TAA. Work from our laboratory has led to the appreciation that a member of Cellular Communication Network (CCN) gene family, CCN3, serves as an important regulator of vascular health. However, the precise physiological role of CCN3 in vivo as well as the fundamental mechanisms responsible for CCN3’s action remain largely undefined. Recently, our preliminary studies suggest that CCN3 serves as an endogenous inhibitor of TAAD. Recently, our preliminary studies suggest that endothelial dysfunction due to CCN3 deficiency predisposes animals to thoracic aortic aneurysm and dissection (TAAD). In a mouse model of Marfan syndrome (Fbn1mgR/mgR), global deficiency of CCN3 deficiency exacerbates thoracic aortic aneurysm (TAA) in Marfan mice characterized by increased aortic root and ascending thoracic aortic dilation, elevated incidence of vessel dissection, and, as a consequence, enhanced mortality. Similar findings were obtained when challenging animals with angiotensin II (Ang II). Endothelial restricted knockout mice (EC CCN3-/-) subjected to Ang II infusion exhibited augmented aortic root and thoracic aortic dilation along with an elevated severity of aortic wall destruction. Mechanistically, our initial bulk RNAseq studies suggested that loss of CCN3 perturbs vascular junction and causes aberrant activation of signaling pathways involved in inflammation. Our subsequent in vivo and in vitro studies further support that key factors secondary to CCN3 deficiency (endothelial barrier disruption, inflammation, reactive oxygen species (ROS)) cause endothelial dysfunction and play a pivotal role in TAAD development and progression. These observations provide the foundation for the central hypotheses of this application: CCN3 serves as a critical physiological regulator for the maintenance of endothelial function essential for the prevention of TAAD. Studies in this proposal will rigorously address this hypothesis. The role of endothelial CCN3 in mitigating TAAD will be fully characterized. Mechanistic basis of how CCN3 deficiency leads to endothelial dysfunction will be investigated. The results of these studies will elucidate the role of CCN3 in controlling endothelial function and the mechanisms underlying its ability to promote endothelial barrier integrity and limit inflammation.

概括主动脉稳态对于血管健康至关重要血管内皮是一个重要的器官，其健康状况至关重要。对正常血管生理至关重要；当失调时，它成为发病机制的关键因素越来越多的证据表明内皮细胞（EC）在多种血管疾病中发挥着重要作用。在胸主动脉瘤和夹层（TAAD）的发生和进展中的作用未被充分认识。最值得注意的是，屏障完整性受损被认为是 TAA 发展的先兆。我们实验室的工作引起了蜂窝通信网络 (CCN) 成员的赞赏基因家族 CCN3 是血管健康的重要调节因子，但其精确的生理功能却受到影响。 CCN3 在体内的作用以及负责 CCN3 作用的基本机制在很大程度上仍然存在最近，我们的初步研究表明 CCN3 是 TAAD 的内源性抑制剂。最近，我们的初步研究表明，CCN3 缺乏导致的内皮功能障碍容易导致在马凡综合征小鼠模型中，动物出现胸主动脉瘤和夹层（TAAD）。 (Fbn1mgR/mgR)，CCN3 的整体缺乏会加剧马凡的胸主动脉瘤 (TAA) 以主动脉根部增加和升胸主动脉扩张为特征的小鼠，发生率升高血管解剖，因此，死亡率增加时也得到了类似的结果。用血管紧张素 II (Ang II) 挑战动物 (EC CCN3-/-)。接受 Ang II 输注显示主动脉根部增强、胸主动脉扩张以及血压升高从机制上讲，我们最初的大量 RNAseq 研究表明，主动脉壁破坏的严重性。 CCN3 扰乱血管连接并导致参与信号通路的异常激活我们随后的体内和体外进一步研究支持 CCN3 继发的关键因素。缺乏（内皮屏障破坏、炎症、活性氧（ROS））会导致内皮细胞这些观察结果提供了 TAAD 的功能障碍并在 TAAD 的发展和进展中发挥关键作用。本申请的中心假设的基础：CCN3 作为关键的生理调节因子本提案中的研究将维持内皮功能对于预防 TAAD 至关重要。严格地解决这一假设将充分表征内皮 CCN3 在缓解 TAAD 中的作用。将研究 CCN3 缺乏如何导致内皮功能障碍的机制基础。这些研究将阐明CCN3在控制内皮功能中的作用及其机制其促进内皮屏障完整性和限制炎症能力的基础。