PP2A attenuates thoracic aneurysm and dissection in mouse models of Marfan syndrome [RNA-seq]. PP2A attenuates thoracic aneurysm and dissection in mouse models of Marfan syndrome [RNA-seq]

Recent studies show that hyperactivation of mTOR signaling plays a causal role in the development of thoracic aortic aneurysm (TAA) and dissection (AAD). Modulation of Protein phosphatase 2A (PP2A) activity has been shown to be of significant therapeutic value. In light of the effects that PP2A can exert on mTOR pathway, we hypothesized that PP2A activation by small molecule activators of PP2A (SMAPs) could mitigate AA progression in Marfan Syndrome (MFS). Overall design: Fbn1mgR/mgR mice, which has under-expression of Fbn1 gene, were obtained from the Jackson Laboratory (JAX stock #005704). A 5mg/kg dose of DT-061 was given orally twice a day to mice starting at the age of 5 weeks (Fbn1mgR/mgR). DT-061 was prepared in a N,N-dimethylacetamide/Kolliphor HS-15/diH20 solution. The control mice were orally given vehicle solution along the same schedule. After 4 weeks of treatment, total RNAs were extracted from ascending aortas in mice and was sent for bulk RAN-seq.

现有研究表明，mTOR信号通路过度激活在胸主动脉瘤（thoracic aortic aneurysm, TAA）与主动脉夹层（aortic dissection, AAD）的发生发展中扮演因果性角色。调节蛋白磷酸酶2A（Protein phosphatase 2A, PP2A）的活性已被证实具备显著治疗价值。鉴于PP2A对mTOR通路的调控效应，我们提出假说：通过小分子PP2A激活剂（small molecule activators of PP2A, SMAPs）激活PP2A，可延缓马凡综合征（Marfan Syndrome, MFS）小鼠的动脉瘤进展。实验设计：本研究采用的Fbn1基因低表达Fbn1mgR/mgR小鼠购自杰克逊实验室（Jackson Laboratory, JAX库存编号：005704）。自小鼠5周龄起，每日两次经口给予5mg/kg的DT-061，该药物配制于N,N-二甲基乙酰胺/Kolliphor HS-15/双蒸水（diH2O）混合溶剂中。对照组小鼠按照相同给药方案经口给予等体积载体溶液。连续给药4周后，提取小鼠升主动脉组织的总RNA并开展批量RNA测序（bulk RNA-seq）。