CCN3 and aortic aneurysm

CCN3 和主动脉瘤

• 批准号: 8851671
• 负责人: Zhiyong Lin
• 金额: $ 39.03万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8851671
• 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; Health; 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; reconstitution; research study; transcriptome sequencing; vascular inflammation

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发挥重要作用。主动脉壁结构和内稳态的维持涉及主要结构成分及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永久性扩张，称为主动脉瘤（AA）；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，主动脉局部炎症、细胞外基质断裂和平滑肌细胞丢失是AA发生和发展的主要特征。两个胸椎的病变