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）：主动脉壁是一种高度组织和调节的结构，在独特的血液动力学环境中执行必不可少的功能。维持主动脉壁结构和稳态涉及主要结构成分与其细胞成分之间的相互作用 - 血管平滑肌细胞（SMC）。这些相互作用以遗传和/或环境因素为继发的这些相互作用可能导致永久性扩张称为主动脉瘤（AA）；一种占全球死亡人数2％的疾病。从临床，病理和实验研究中收集的见解表明，主动脉的局部炎症，细胞外基质的碎片化以及平滑肌细胞的丧失是启动和进展AA的核心特征。这些病变都在胸腔中 腹主动脉可能会恶化，导致解剖和 /或破裂。虽然管理AA形成的分子途径仍然很少理解，但积累的证据表明激活肾素 - 血管紧张素系统（RAS）是导致AA病发病机理的重要促进者。但是，目前针对该途径的药物疗法和其他针对的药物仅表现出适度的治疗益处，这表明需要对该疾病实体的病理生物学有更多的见解才能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传导蛋白，能够介导多种生物学功能。但是，这些蛋白质在脉管系统中的生理功能在很大程度上是未知的。申请人实验室的新生观察结果将CCN3（CCN家族的成员）识别为AA形成的基本调节剂。在血管紧张素II（ANG II）输注后，发现CCN3表达在啮齿动物主动脉中大大降低，在人AA组织中概括的发现。在ANG II输注后，从系统地缺乏CCN3的小鼠出现的CCN3发育为特征，其特征是弹性蛋白片段化，血管炎症/解剖和SMC凋亡。此外，CCN3缺乏症显着增加了NFKB的核水平，NFKB是血管SMC炎症和存活率的关键调节剂。最后，我们将类似于Kruppel的因子15（KLF15）鉴定为AA形成的基本决定因素，是SMC中CCN3表达的上游调节剂。总的来说，这些观察结果提供了有说服力的证据，暗示了CCN3​​在AA疾病发病机理中的先前未识别的作用。为了更好地理解CCN3在动脉瘤生物学中的作用，提出了三种鲁棒和相互关联的目标。在AIM 1中，我们将充分表征CCN3在主动脉动脉瘤形成中的作用。在AIM 2中，我们试图阐明CCN3缺乏导致主动脉瘤发育的分子机制。最后，在AIM 3中，我们将确定CCN3在KLF15-KO动物中的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了基础。