KLF15 in vascular disease

描述（由申请人提供）：主动脉壁是一个严格调节的结构，在独特的血流动力学环境中发挥重要功能。主动脉壁内稳态涉及主要结构成分与其主要细胞成分血管平滑肌细胞之间的相互作用。继发于遗传和/或环境因素的这些体内平衡机制的扰动可导致永久性扩张，称为主动脉动脉瘤（AA）。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、细胞外基质碎裂和平滑肌细胞丧失是AA的主要特征。这些病变可能发生在主动脉树的胸部和腹部区域，并可能恶化为血管剥离和/或破裂，这是发病率和死亡率的重要来源。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病发病机制的重要因素。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效果，这表明需要对这种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。我们小组最近发表的研究成果以及本应用程序提供的初步观察结果表明，转录因子kruppel样因子15 （KLF15）是AA形成的重要调节因子。在血管紧张素II （Ang II）输注后，KLF15在人AA组织和小鼠主动脉中的表达明显降低。缺乏KLF15的小鼠在输注Ang II后发生以弹性蛋白断裂、血管炎症/夹层和SMC凋亡为特征的AA。在机制上，我们的研究表明，KLF15缺陷增加了p53的水平和活性，p53是平滑肌细胞炎症和存活的关键调节因子。观察到KLF15和p53的复合缺乏可改善AA的形成，从而强调了p53的重要性。总的来说，这些观察结果提供了令人信服的证据，表明以前未被认识到的转录轴- KLF15/p53 -对乳腺癌至关重要

DESCRIPTION (provided by applicant): The aortic wall is a tightly regulated structure that performs essential functions in a unique hemodynamic environment. Aortic wall homeostasis involves interactions between major structural components and its predominant cellular constituent - the vascular smooth muscle cell. Perturbation of these homeostatic mechanisms secondary to genetic and/or environmental factors can lead to permanent dilatations termed aorta aneurysms (AA). Insights gleaned from clinical, pathologic, and experimental studies indicate that local inflammation of the aorta, fragmentation of the extracellular matrix, and loss f smooth muscle cells are central features of AA. These lesions may occur in both the thoracic and abdominal regions of the aortic tree and can deteriorate to vascular dissection and/or rupture that constitute a significant source of morbidity and mortality. 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 effects suggesting that greater insights into the pathobiology of this disease entity are required to develop effective therapies. Recently published work from our group coupled with nascent observations provided in this application identify the transcription factor Kruppel-like factor 15 (KLF15) as an essential regulator of AA formation. KLF15 expression was found to be strongly reduced in human AA tissues and in aortas of mice following angiotensin II (Ang II) infusion. Mice deficient in KLF15 develop AA characterized by elastin fragmentation, vascular inflammation/dissection, and SMC apoptosis following Ang II infusion. Mechanistically, our studies reveal that KLF15 deficiency increased the levels and activity of p53, a key regulator of smooth muscle cell inflammation and survival. The importance of p53 is underscored by the observation that compound deficiency of KLF15 and p53 ameliorates AA formation. Collectively, these observations provide cogent evidence implicating a previously unrecognized transcriptional axis - that of KLF15/p53 - as critical to the pathogenesis of AA disease. To better understand the role of KLF15 in aneurysmal biology three robust and interrelated aims are proposed. In aim 1, we will assess the effect of vascular specific manipulation of the KLF15-p53 axis on AA formation. In aim 2, we seek to elucidate the molecular mechanism underlying KLF15-mediated alterations in p53 acetylation and activity in vitro. And finally, in aim 3, we will determine the in vivo role of KLF15-dependent regulation of p53 acetylation/activity in AA formation. Collectively, these studies will provide novel insights regarding a previously unappreciated transcriptional pathway governing aortic aneurysm development. Further, the results of these studies may provide the foundation for novel approaches to the treatment of this highly morbid and mortal disease. PUBLIC HEALTH RELEVANCE: Aortic aneurysms are a major cause of morbidity and mortality worldwide. The mechanisms underlying the development of aortic aneurysms remain poorly understood and, consequently, hampered the development of effective medical therapies. Recent studies from our group have identified a previously unrecognized molecular pathway regulating aneurysm formation. This proposal seeks to develop a detailed understanding of this pathway with the goal of developing novel therapies for the treatment of this highly mortal condition.