KLF15 in vascular disease

KLF15 在血管疾病中的作用

基本信息

批准号：
8319788
负责人：
MUKESH Kumar JAIN
金额：
$ 49.49万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8319788
关键词：
Abdomen Acetylation Aneurysm Angiotensin II Animals Aorta Aortic Aneurysm Apoptosis Biology Blood Vessels Cells ChIP-seq Chest Clinical Coupled Deacetylase Deacetylation Development Dilatation - action Disease Dissection EP300 gene Elastin Environment Environmental Risk Factor Extracellular Matrix Foundations Genetic Glean Goals Homeostasis Human Inflammation Infusion procedures Kruppel-like transcription factors Lead Lesion Mediating Medical Molecular Morbidity - disease rate Mus Pathogenesis Pathologic Pathway interactions Pharmacotherapy Phenotype Post-Translational Protein Processing Publishing RNA Regulation Regulatory Pathway Relative (related person)Renin-Angiotensin System Role Rupture Secondary to Smooth Muscle Myocytes Source Structure Therapeutic Thoracic aorta Tissues Transgenic Organisms Trees Vascular Diseases Work abdominal aorta base effective therapy genome-wide hemodynamics in vitro activity in vivo insight mortality mutant novel novel strategies overexpression p300/CBP-Associated Factor research study vascular inflammation

项目摘要

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.

描述（由申请人提供）：主动脉壁是一种受到严格调控的结构，在独特的血流动力学环境中执行基本功能。主动脉壁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）的永久性扩张。从临床、病理和实验研究中收集到的见解表明，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，并且可能恶化为血管夹层和/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 疾病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疗法仅表现出有限的效果，这表明需要更深入地了解该疾病实体的病理学才能开发有效的疗法。我们小组最近发表的工作以及本申请中提供的新观察结果确定转录因子 Kruppel 样因子 15 (KLF15) 是 AA 形成的重要调节因子。研究发现，在输注血管紧张素 II (Ang II) 后，人类 AA 组织和小鼠主动脉中的 KLF15 表达显着降低。缺乏 KLF15 的小鼠在输注 Ang II 后会出现以弹性蛋白断裂、血管炎症/解剖和 SMC 凋亡为特征的 AA。从机制上讲，我们的研究表明，KLF15 缺乏会增加 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。 KLF15 和 p53 的复合缺乏会改善 AA 的形成，这一观察结果强调了 p53 的重要性。总的来说，这些观察结果提供了有力的证据，表明以前未被识别的转录轴——KLF15/p53——对于 AA病的发病机制。为了更好地理解 KLF15 在动脉瘤生物学中的作用，提出了三个强有力且相互关联的目标。在目标 1 中，我们将评估 KLF15-p53 轴的血管特异性操作对 AA 形成的影响。在目标 2 中，我们试图阐明 KLF15 介导的 p53 乙酰化和体外活性改变的分子机制。最后，在目标 3 中，我们将确定 KLF15 依赖性调节 p53 乙酰化/活性在 AA 形成中的体内作用。总的来说，这些研究将为以前未被重视的控制主动脉瘤发展的转录途径提供新的见解。此外，这些研究的结果可能为治疗这种高度发病和致命疾病的新方法奠定基础。公共卫生相关性：主动脉瘤是全世界发病和死亡的主要原因。主动脉瘤形成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发现了一种以前未被认识的调节动脉瘤形成的分子途径。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疗法。