CCN3 and aortic aneurysm

描述(申请人提供)：主动脉壁是一种高度组织和调节的结构，在独特的血流动力学环境中执行基本功能。维持主动脉壁结构和动态平衡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。遗传和/或环境因素继发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%。临床、病理和实验研究表明，主动脉局部炎症、细胞外基质碎裂和平滑肌细胞丢失是AA发生和发展的主要特征。这些在胸部和胸腔的损伤 腹主动脉可能恶化，导致夹层和/或破裂。尽管控制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疾病发病的重要因素。然而，目前针对这一途径和其他途径的药物治疗仅显示出适度的治疗益处，这表明需要对这种疾病的病理生物学有更深入的了解，以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，具有多种生物学功能。然而，这些蛋白质在血管系统中的生理功能在很大程度上是未知的。来自申请人实验室的初步观察表明，CCN3(CCN家族的成员)是AA形成的重要调节因子。血管紧张素II(Ang II)注射后，啮齿类动物主动脉中CCN3的表达显著减少，这一发现在人类AA组织中得到了概括。系统性缺乏CCN3的小鼠在注射Ang II后出现以弹性蛋白断裂、血管炎症/夹层和SMC凋亡为特征的再生障碍性贫血。此外，CCN3缺乏显著增加了NFkB的核水平，NFkB是血管SMC炎症和生存的关键调节因子。最后，我们发现Kruppel样因子15(KLF15)是AA形成的关键决定因素，是SMC中CCN3表达的上游调节因子。总而言之，这些观察结果提供了令人信服的证据，表明CCN3在再障疾病的发病机制中发挥了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，我们提出了三个可靠且相互关联的目标。在目标1中，我们将充分研究CCN3在主动脉瘤形成中的作用。在目标2中，我们试图阐明CCN3缺乏导致主动脉瘤发生的分子机制。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提供基础。

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.