KLF15 in vascular disease

描述（由申请人提供）：主动脉壁是一种严格调节的结构，在独特的血液动力学环境中执行基本功能。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/或环境因素的这些稳态机制的扰动可导致称为主动脉瘤（AA）的永久性动脉瘤。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的中心特征。这些病变可能发生在主动脉树的胸部和腹部区域，并可能恶化为血管夹层和/或破裂，构成发病率和死亡率的重要来源。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表现出适度的效果，这表明需要对该疾病实体的病理生物学有更深入的了解才能开发有效的治疗方法。我们小组最近发表的工作加上本申请中提供的新生观察结果将转录因子Kruppel样因子15（KLF 15）鉴定为AA形成的重要调节因子。KLF 15的表达被发现在人AA组织和血管紧张素II（Ang II）输注后的小鼠动脉中强烈降低。缺乏KLF 15的小鼠在血管紧张素II输注后发生AA，其特征在于弹性蛋白断裂、血管炎症/夹层和SMC凋亡。从机制上讲，我们的研究表明，KLF 15缺乏增加了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。通过观察到KLF 15和p53的复合缺陷改善AA形成，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-KLF 15/p53 -对肿瘤的发生至关重要。 AA疾病的发病机制。为了更好地理解KLF 15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，我们将评估血管特异性操纵KLF 15-p53轴对AA形成的影响。在目标2中，我们试图阐明KLF 15介导的p53乙酰化和活性改变的分子机制。最后，在目标3中，我们将确定KLF 15依赖性调节AA形成中p53乙酰化/活性的体内作用。总的来说，这些研究将提供新的见解，关于以前不受重视的转录途径控制主动脉瘤的发展。此外，这些研究的结果可能为治疗这种高度病态和致命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。对主动脉瘤发展的机制仍然知之甚少，因此阻碍了有效药物治疗的发展。我们小组最近的研究已经确定了一个以前未被认识的调节动脉瘤形成的分子通路。该提案旨在详细了解这一途径，目标是开发治疗这种高度致命疾病的新型疗法。

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.