KLF15 in vascular disease

描述(申请人提供)：主动脉壁是一种严格调节的结构，在独特的血流动力学环境中发挥基本功能。主动脉壁稳态涉及主要结构成分和其主要细胞成分--血管平滑肌细胞之间的相互作用。继发于遗传和/或环境因素的这些动态平衡机制的扰动可导致永久性扩张，称为主动脉瘤(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丢失是再障的主要特征。这些病变可发生在胸主动脉树和腹主动脉树区域，并可恶化为血管夹层和/或破裂，构成发病率和死亡率的重要来源。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温和的效果，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。我们小组最近发表的工作与本申请中提供的新观察相结合，确定转录因子Kruppel-like factor15(KLF15)是AA形成的重要调节因子。血管紧张素II(Ang II)注射后，KLF15在人AA组织和小鼠主动脉中的表达显著降低。KLF15基因缺陷的小鼠在注射Ang II后出现以弹性蛋白断裂、血管炎症/夹层和SMC凋亡为特征的再障。从机制上讲，我们的研究表明，KLF15缺乏增加了P53的水平和活性，P53是平滑肌细胞炎症和生存的关键调节因子。KLF15和P53的复合缺失可以改善AA的形成，这一观察结果突显了P53的重要性。总而言之，这些观察提供了令人信服的证据，表明先前未被识别的转录轴-KLF15/P53-对 再障的发病机制。为了更好地理解KLF15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，我们将评估血管特异性操作KLF15-P53轴对AA形成的影响。在目标2中，我们试图阐明KLF15介导的P53乙酰化和体外活性变化的分子机制。最后，在目标3中，我们将确定KLF15依赖的P53乙酰化/活性调节在AA形成中的体内作用。总而言之，这些研究将提供关于一种以前未被认识的主动脉瘤发生的转录途径的新见解。此外，这些研究的结果可能为治疗这种高度病态和致命性疾病的新方法提供基础。 公共卫生相关性：主动脉瘤是全球发病率和死亡率的主要原因。主动脉瘤发生的潜在机制仍然知之甚少，因此阻碍了有效药物治疗的发展。我们小组最近的研究发现了一种以前未知的调节动脉瘤形成的分子途径。这项提议寻求对这一途径的详细了解，目标是开发治疗这种高度致命的疾病的新疗法。

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.