CCN3 and aortic aneurysm

CCN3 和主动脉瘤

基本信息

批准号：
8470031
负责人：
Zhiyong Lin
金额：
$ 37.69万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8470031
关键词：
Accounting Address Aneurysm Angiotensin II Animals Aorta Aortic Aneurysm Apoptosis Biology Blood Vessels Bone Marrow Transplantation Cells Cessation of life Clinical Data Defect Development Dilatation - action Disease Dissection Elastases Elastin Environment Environmental Risk Factor Extracellular Matrix Family Foundations Genes Genetic Glean Hematopoietic Homeostasis Human Inflammation Inflammatory Infusion procedures Knockout Mice Laboratories Lead Lesion Maintenance Mediating Medical Modeling Molecular Morbidity - disease rate Mus Nuclear Operative Surgical Procedures Oxidative Stress Pathogenesis Pathologic Pathway interactions Perfusion Pharmacotherapy Phenotype Physiological Protein Family Renin-Angiotensin System Rodent Role Rupture Secondary to Signal Pathway Signaling Protein Smooth Muscle Myocytes Source Structure Therapeutic Thoracic aorta Tissues abdominal aorta base effective therapy gain of function genome-wide hemodynamics insight lentiviral-mediated member mortality novel novel strategies overexpression protein function public health relevance reconstitution research study transcriptome sequencing vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): The aortic wall is a highly organized and regulated structure that performs essential functions in a unique hemodynamic milieu. Maintenance of aortic wall structure and homeostasis involves interactions between major structural components and its cellular constituent - the vascular smooth muscle cell (SMC). Perturbation of these interactions secondary to genetic and/or environmental factors can lead to permanent dilatations termed aortic aneurysms (AA); a disease that accounts for 2% of deaths worldwide. Insights gleaned from clinical, pathologic, and experimental studies indicate that local inflammation of the aorta, fragmentation of the extracellular matrix, and loss of smooth muscle cells are central features in the initiation and progression AA. These lesions in both the thoracic and abdominal aorta can deteriorate resulting in dissection and /or rupture. While the molecular pathways governing AA formation remain poorly understood, accumulating evidence implicates activation of the renin-angiotensin system (RAS) as an important contributor to the pathogenesis of AA disease. However, current pharmacotherapies targeting this pathway and others have demonstrated only modest therapeutic benefit suggesting that greater insights into the pathobiology of this disease entity are required to develop effective treatments. CCN (Cyr61, Ctgf, Nov) family proteins are a group of secreted extracellular matrix-associated signaling proteins that are capable of mediating diverse biologic functions. However, the physiological functions of these proteins in the vasculature are largely unknown. Nascent observations from the applicant's laboratory identify CCN3 (a member of CCN family) as an essential regulator of AA formation. CCN3 expression was found to be strongly reduced in the rodent aorta following angiotensin II (Ang II) infusion, findings recapitulated in human AA tissues. Mice systemically deficient in CCN3 develop AA characterized by elastin fragmentation, vascular inflammation/dissection, and SMC apoptosis following Ang II infusion. Additionally, CCN3 deficiency dramatically increased the nuclear levels of NFkB, a key regulator of vascular SMC inflammation and survival. Lastly, we identify Kruppel-like factor 15 (KLF15), an essential determinant of AA formation, as an upstream regulator of CCN3 expression in SMC. Collectively, these observations provide cogent evidence implicating a previously unrecognized role for CCN3 in the pathogenesis of AA disease. To better understand the role of CCN3 in aneurysmal biology three robust and interrelated aims are proposed. In Aim 1, we will fully characterize the role of CCN3 in aortic aneurysm formation. In Aim 2, we seek to elucidate the molecular mechanism by which CCN3 deficiency leads to aortic aneurysm development. And finally, in Aim 3, we will determine the importance of CCN3 in AA formation in KLF15-KO animals. The results of these studies may provide the foundation for novel approaches to the treatment of this disease.

描述（由申请人提供）：主动脉壁是一个高度组织和调节的结构，在独特的血流动力学环境中执行基本功能。主动脉壁结构和稳态的维持涉及主要结构成分与其细胞成分——血管平滑肌细胞（SMC）之间的相互作用。继发于遗传和/或环境因素的这些相互作用的扰动可导致称为主动脉瘤（AA）的永久性扩张；这种疾病占全球死亡人数的 2%。从临床、病理和实验研究中收集到的见解表明，主动脉的局部炎症、细胞外基质的破碎和平滑肌细胞的损失是 AA 起始和进展的核心特征。这些病变位于胸部腹主动脉可能会恶化，导致夹层和/或破裂。虽然控制 AA 形成的分子途径仍然知之甚少，但越来越多的证据表明肾素-血管紧张素系统 (RAS) 的激活是 AA 疾病发病机制的重要贡献者。然而，目前针对该途径和其他途径的药物疗法仅证明了有限的治疗益处，这表明需要更深入地了解该疾病实体的病理学来开发有效的治疗方法。 CCN (Cyr61、Ctgf、Nov) 家族蛋白是一组分泌的细胞外基质相关信号蛋白，能够介导多种生物功能。然而，这些蛋白质在脉管系统中的生理功能很大程度上是未知的。申请人实验室的初步观察结果表明CCN3（CCN家族的成员）是AA形成的重要调节因子。研究发现，在注射血管紧张素 II (Ang II) 后，啮齿动物主动脉中的 CCN3 表达显着降低，这一发现在人类 AA 组织中也得到了重现。系统性缺乏 CCN3 的小鼠会在 Ang II 输注后出现以弹性蛋白断裂、血管炎症/解剖和 SMC 凋亡为特征的 AA。此外，CCN3 缺陷显着增加了 NFkB 的核水平，NFkB 是血管 SMC 炎症和存活的关键调节因子。最后，我们确定了 Kruppel 样因子 15 (KLF15)，AA 形成的重要决定因素，作为 SMC 中 CCN3 表达的上游调节因子。总的来说，这些观察结果提供了有力的证据，表明 CCN3 在 AA 疾病的发病机制中发挥着以前未被认识到的作用。为了更好地理解 CCN3 在动脉瘤生物学中的作用，提出了三个强有力且相互关联的目标。在目标 1 中，我们将充分描述 CCN3 在主动脉瘤形成中的作用。在目标 2 中，我们试图阐明 CCN3 缺陷导致主动脉瘤发展的分子机制。最后，在目标 3 中，我们将确定 CCN3 在 KLF15-KO 动物 AA 形成中的重要性。这些研究的结果可能为治疗这种疾病的新方法奠定基础。