Role of Protein Phosphatase 2A in Aortic Aneurysm

项目摘要 由遗传缺陷或暴露于环境危险因素引起的主动脉稳态破坏导致 主动脉的局部异常增宽，称为主动脉瘤（AA）的退行性疾病状态。 实验研究表明，AA与受损的平滑肌收缩性、细胞外 基质（ECM）恶化，以及与白细胞浸润相关的血管炎症增加。这 病理状态以血管壁的弱化和进行性扩张而达到高潮，如果不治疗， 导致通常致命的夹层和/或破裂。尽管发病率和死亡率很高， 对于主动脉瘤，药物治疗仍然不足，不幸的是，紧急手术是最重要的。 治疗选择因此，必须解决这一重要的未满足的临床需求，可能通过 开发新的药物治疗以及更有效的管理策略， 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 AA形成和发展的机制。为此，该项目旨在开发一种有前途的 一组称为蛋白磷酸酶2A（SMAPs）的小分子激活剂的治疗剂， 治疗主动脉瘤，并获得PP 2A在其发病机制中的作用的机制见解。 疾病 可逆的蛋白质磷酸化在生物学功能中起着普遍存在的细胞调节作用。的 蛋白磷酸化的调节涉及蛋白激酶和磷酸化酶活性之间的平衡。 蛋白磷酸酶尽管对异常激酶活性如何促进 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（PP 2A）是一种具有显著丝氨酸/苏氨酸磷酸酶活性的全酶 在哺乳动物细胞中的活性。PP 2A活性的恢复已显示出显著的治疗价值， 然而，直接激活PP 2A的药学上易处理的方法仍然是难以捉摸的。最近的观察 我们实验室的研究表明，在人类和小鼠主动脉平滑肌细胞中PP 2A活性的严重丧失， 组织中此外，口服生物可利用的PP 2A小分子活化剂（SMAPs）， 在马凡氏综合征（MFS）和血管紧张素II（Ang II）诱导的AA进展中， 腹主动脉瘤（AAA）的动物模型。这些观察结果为两个主要的 该应用的假设：（1）PP 2A失活与主动脉瘤（AA）病因有关，（2） PP 2A的激活可作为限制AA进展的新策略。在本提案中，我们将利用 药理学和遗传学的方法来剖析的分子基础和功能的后果， PP 2A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.