Role of Protein Phosphatase 2A in Aortic Aneurysm

项目摘要 遗传缺陷或暴露于环境风险因素导致的主动脉内稳态紊乱导致 局限性的主动脉异常增宽，一种称为主动脉瘤(AA)的退行性疾病状态。 实验研究表明，AA与细胞外血管收缩功能受损有关 基质(ECM)恶化，与白细胞浸润相关的血管炎症增加。这 病理状态以血管壁变弱和进行性扩张为高潮，如果不治疗， 通常会导致致命的夹层和/或破裂。尽管相关的发病率和死亡率很高 对于主动脉瘤，药物治疗仍然不够，不幸的是，紧急手术是首要任务。 治疗选择。因此，必须解决这一重要的未得到满足的临床需求，可能是通过 开发新的药物疗法以及更有效的管理战略来对抗 这种可怕的疾病。然而，一个关键的障碍在于对分子的不完全理解。 再生障碍性贫血形成和发展的机制。为此，本项目寻求开发一种前景看好的 一组被称为蛋白磷酸酶小分子激活剂(SMAPs)的治疗剂，用于治疗 治疗主动脉瘤并从机制上深入了解PP2A在主动脉瘤发病机制中的作用 疾病。 可逆的蛋白质磷酸化在生物功能中起着普遍存在的细胞调节作用。这个 蛋白磷酸化的调节涉及蛋白激酶和蛋白激酶活性之间的平衡。 蛋白磷酸酶。尽管人们对异常的激酶活性如何起作用有很大的了解 对于人类心血管疾病，磷酸酶在这一领域的调节和治疗潜力仍然存在 开发不足。蛋白磷酸酶2A(PP2A)是一种具有显著丝氨酸/苏氨酸磷酸酶活性的全酶 哺乳动物细胞中的活动。PP2A活性的恢复已被证明具有显著的治疗价值， 然而，直接激活PP2A的药学上容易掌握的方法仍然难以捉摸。最近的观察结果 来自我们实验室的研究表明，在人和小鼠的主动脉瘤中，PP2A活性的严重丧失 纸巾。此外，口服生物可用PP2A小分子激活剂(SMAPs)， 显著抑制马凡综合征(MFS)和血管紧张素II(Ang II)诱导的AA进展 腹主动脉瘤(AAA)动物模型。这些观察为以下两个主要观点提供了基础 这一应用的假设：(1)PP2A失活与主动脉瘤(AA)的病因有关；(2) PP2A的激活可能成为限制AA进展的一种新策略。在这项提案中，我们将利用 用药理学和遗传学的方法来分析血管紧张素转换酶的分子基础和功能后果 PP2A在主动脉瘤中的激活/失活。

Project Summary Disruption of aortic homeostasis arising from genetic defects or exposure to environmental risk factors leads to localized abnormal widening of the aorta, a degenerative disease state termed aortic aneurysm (AA). Experimental studies reveal that AA is associated with compromised smooth muscle contractility, extracellular matrix (ECM) deterioration, and increased vascular inflammation associated with leukocyte infiltration. This pathologic state culminates with weakening of the vessel wall and progressive dilatation that, if left untreated, results in an often fatal dissection and/or rupture. Despite the high degree of morbidity and mortality associated with aortic aneurysm, medical treatments remain inadequate and urgent surgery is unfortunately the top therapeutic option. Therefore, it is imperative to address this important unmet clinical need, potentially by the development of novel pharmacologic therapies as well as more effective management strategies to combat this dreadful disease. However, a critical roadblock lies in the incomplete understanding of the molecular mechanisms governing AA formation and progression. To that end, this project seeks to develop a promising group of therapeutic agents termed small molecule activators of Protein Phosphatase 2A (SMAPs) for the treatment of aortic aneurysm and gain mechanistic insights into the role of PP2A in the pathogenesis of this disease. Reversible protein phosphorylation plays a ubiquitous cellular regulatory role in biological functions. The regulation of protein phosphorylation involves a balance between the activities of both protein kinases and protein phosphatases. Although there is a significant understanding of how aberrant kinase activity contributes to human cardiovascular disease, the regulation and therapeutic potential of phosphatases in this area remains under-explored. Protein phosphatase 2A (PP2A) is a holoenzyme with notable serine/threonine phosphatase activity in mammalian cells. Restoration of PP2A activity has been shown to be of significant therapeutic value, however pharmaceutically tractable approaches to directly activate PP2A remain elusive. Recent observations from our laboratory revealed that a profound loss of PP2A activity in both human and mouse aortic aneurysmal tissues. Furthermore, administration of the orally bioavailable small molecule activator of PP2A (SMAPs), markedly suppressed AA progression in both Marfan's syndrome (MFS) and angiotensin II- (Ang II) induced abdominal aortic aneurysm (AAA) in animal models. These observations provide the basis for the two main hypotheses for this application: (1) PP2A inactivation is involved in aortic aneurysm (AA) etiology and (2) activation of PP2A may serve as a novel strategy to limit AA progression. In this proposal, we will leverage both pharmacologic and genetic approaches to dissect the molecular basis and functional consequences of PP2A activation/inactivation on aortic aneurysm.