Role of Protein Phosphatase 2A in Aortic Aneurysm

蛋白磷酸酶 2A 在主动脉瘤中的作用

• 批准号: 10317079
• 负责人: Zhiyong Lin
• 金额: $ 54.85万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-16 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10317079
• 关键词: Abdominal Aortic Aneurysm; Address; Aneurysm; Angiotensin II; Animal Model; Animals; Aorta; Aortic Aneurysm; Area; Biochemical; Biological Process; Biology; Cardiovascular Diseases; Catalytic Domain; Cell physiology; Chest; Clinical; Data; Degenerative Disorder; Dependence; Deterioration; Development; Dilatation - action; Disease; Disease model; Dissection; Environmental Risk Factor; Equilibrium; Etiology; Exposure to; Extracellular Matrix; Foundations; Genetic; Glean; Histologic; Holoenzymes; Homeostasis; Human; Infiltration; Laboratories; Lead; Left; Leukocytes; Mammalian Cell; Marfan Syndrome; Mediating; Medical; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Operative Surgical Procedures; Oral Administration; Pathogenesis; Pathologic; Pathology; Pharmacologic Substance; Pharmacology; Pharmacotherapy; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Play; Property; Protein Kinase; Protein Serine/Threonine Phosphatase; Protein phosphatase; Regulation; Research; Role; Rupture; Smooth Muscle; Smooth Muscle Myocytes; Therapeutic; Therapeutic Agents; Therapeutic Effect; Thoracic Aortic Aneurysm; Tissues; attenuation; clinical development; combat; efficacy testing; experimental study; genetic approach; insight; mortality; mouse model; novel; novel strategies; novel therapeutics; phosphoproteomics; protein activation; protein phosphatase 2A regulatory subunit 65 kDa; restoration; small molecule; transcriptome sequencing; vascular inflammation

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.

项目概要 由于遗传缺陷或暴露于环境危险因素而引起的主动脉稳态破坏会导致 主动脉局部异常扩张，一种称为主动脉瘤（AA）的退行性疾病状态。 实验研究表明，AA 与平滑肌收缩力受损、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 病理状态最终导致血管壁衰弱和进行性扩张，如果不及时治疗， 导致通常致命的剥离和/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，紧急手术是首要选择 治疗选择。因此，必须解决这一重要的未满足的临床需求，可能由 开发新的药物疗法以及更有效的管理策略来对抗 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。 控制 AA 形成和进展的机制。为此，该项目旨在开发一个有前途的 一组称为蛋白磷酸酶 2A 小分子激活剂 (SMAP) 的治疗剂，用于治疗 主动脉瘤的治疗并深入了解 PP2A 在此发病机制中的作用 疾病。 可逆的蛋白质磷酸化在生物功能中发挥着普遍存在的细胞调节作用。这 蛋白质磷酸化的调节涉及蛋白激酶和蛋白激酶活性之间的平衡 蛋白质磷酸酶。尽管人们对异常激酶活性如何影响有重要的了解 对于人类心血管疾病，磷酸酶在该领域的调节和治疗潜力仍然存在 尚未充分探索。蛋白磷酸酶 2A (PP2A) 是一种具有显着丝氨酸/苏氨酸磷酸酶的全酶 哺乳动物细胞中的活性。 PP2A活性的恢复已被证明具有显着的治疗价值， 然而，直接激活 PP2A 的药物易处理方法仍然难以捉摸。最近的观察 我们实验室的研究表明，人和小鼠的主动脉瘤中 PP2A 活性均严重丧失 组织。此外，口服生物可利用的 PP2A 小分子激活剂（SMAP）， 显着抑制马凡氏综合征 (MFS) 和血管紧张素 II (Ang II) 诱导的 AA 进展 动物模型中的腹主动脉瘤（AAA）。这些观察为以下两个主要方面提供了基础： 该应用的假设：(1) PP2A 失活与主动脉瘤 (AA) 病因有关，(2) PP2A 的激活可能作为限制 AA 进展的新策略。在本提案中，我们将利用 药理学和遗传学方法来剖析分子基础和功能后果 主动脉瘤上的 PP2A 激活/失活。

项目成果

Lulling the Cancer Cell into an Eternal Sleep.

让癌细胞陷入永恒的睡眠。

• 发表时间: 2019
• 影响因子: 11.2
• 作者: Farrington, Caroline C;Narla, Goutham
• 通讯作者: Narla, Goutham

Comment on "PP2A inhibition sensitizes cancer stem cells to ABL tyrosine kinase inhibitors in BCR-ABL human leukemia".

评论“PP2A 抑制使癌症干细胞对 BCR-ABL 人类白血病中的 ABL 酪氨酸激酶抑制剂敏感”。

• 发表时间: 2019
• 影响因子: 17.1
• 作者: Perrotti, Danilo;Agarwal, Anupriya;Lucas, Claire M;Narla, Goutham;Neviani, Paolo;Odero, Maria D;Ruvolo, Peter P;Verrills, Nicole M
• 通讯作者: Verrills, Nicole M

CCN2 deficiency in smooth muscle cells triggers cell reprogramming and aggravates aneurysm development.

平滑肌细胞中的 CCN2 缺陷会触发细胞重编程并加剧动脉瘤的发展。

• 发表时间: 2023-01-10
• 影响因子: 8
• 作者: Wang, Yu;Liu, Xuesong;Xu, Qian;Xu, Wei;Zhou, Xianming;Leask, Andrew;Lin, Zhiyong
• 通讯作者: Lin, Zhiyong

Myeloid CCN3 protects against aortic valve calcification.

髓样 CCN3 可以防止主动脉瓣钙化。

• 发表时间: 2023-01-20
• 作者: Tu, Peinan;Xu, Qian;Zhou, Xianming;Villa;Kumar, Sandeep;Dong, Nianguo;Jo, Hanjoong;Ou, Caiwen;Lin, Zhiyong
• 通讯作者: Lin, Zhiyong

Challenges and Reinterpretation of Antibody-Based Research on Phosphorylation of Tyr307 on PP2Ac.

基于抗体的 PP2Ac 上 Tyr307 磷酸化研究的挑战和重新解释。

• DOI: 10.1016/j.celrep.2020.02.012
• 发表时间: 2020-03-01
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Sahar Mazhar;D. Leonard;Alej;ro Sosa;ro;D. Schlatzer;Dafydd G. Thomas;G. Narla
• 通讯作者: G. Narla