CCN3 and aortic aneurysm

描述（由申请人提供）：主动脉壁是一种高度组织化和调节的结构，在独特的血流动力学环境中发挥重要功能。主动脉壁结构和稳态的维持涉及主要结构组分与其细胞组分-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）的永久性动脉瘤;这种疾病占全球死亡的2%。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、细胞外基质的破碎和平滑肌细胞的损失是AA起始和进展的中心特征。这些病变在胸部 并且腹主动脉可能恶化导致夹层和/或破裂。虽然AA形成的分子途径仍然知之甚少，越来越多的证据表明，激活的肾素-血管紧张素系统（RAS）的AA疾病的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治疗仅显示出适度的治疗益处，这表明需要对该疾病实体的病理生物学有更深入的了解以开发有效的治疗方法。CCN（Cyr 61，Ctgf，Nov）家族蛋白是一类分泌型细胞外基质相关信号蛋白，具有多种生物学功能。然而，这些蛋白质在脉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将CCN 3（CCN家族的成员）鉴定为AA形成的必要调节剂。在啮齿动物主动脉中，血管紧张素II（Ang II）输注后，发现CCN 3表达强烈降低，这一发现在人类AA组织中重现。CCN 3系统性缺陷的小鼠发展AA，其特征在于血管紧张素II输注后弹性蛋白断裂、血管炎症/夹层和SMC凋亡。此外，CCN 3缺乏显著增加了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Kruppel样因子15（KLF 15），AA形成的一个重要决定因素，作为SMC中CCN 3表达的上游调节因子。总的来说，这些观察结果提供了令人信服的证据，表明CCN 3在AA疾病的发病机制中具有以前未被认识到的作用。为了更好地理解CCN 3在细胞生物学中的作用，提出了三个强大且相互关联的目标。在目标1中，我们将充分描述CCN 3在主动脉瘤形成中的作用。在目标2中，我们试图阐明CCN 3缺乏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CCN 3在KLF 15-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.