Cyclin-dependent kinase (CDK)19-mediated vein graft intimal hyperplasia

静脉搭桥手术仍然是闭塞性动脉疾病血管再通治疗的金标准； 然而，高达50%的静脉移植物(VGS)将在术后10年内闭塞或失败。VG故障(VGF) 发生在术后30天后，主要是由于VG内膜增生或新生血管形成所致，其中 主要细胞类型是高度迁移、增殖和分泌型的血管平滑肌细胞(SMCs)， 即合成SMC。最近，我们的谱系追踪研究表明，VG新生内膜SMC主要是 通过称为血管SMC脱分化或表型分化的过程从预先存在的血管SMC分化而来 调制/转换。然而，血管SMC脱分化的分子机制仍远未完全阐明。 全面了解。因此，靶向血管SMC脱分化治疗VGF不是 但已经确立了。在这一点上，我们发现细胞周期蛋白依赖蛋白19(CDK19)，一个IDG合格的蛋白开放 在RFA-RM-22-024下研究，可能是血管SMC脱分化为合成SMC的介质 VG血管内膜增生。我们的初步研究使用了CDK8/19基因敲除、CDK8/19 Duo抑制剂和CDK8 SMC- 体外和体内的特异性敲除(KO)方法有力地支持了CDK19控制的工作假说 血管SMC脱分化为合成SMC的一组独特基因的表达 对VGF的贡献。为了证实这一假设，我们提出了两个具体目标如下：目标1是从基因上 询问CDK19操作的信号网络以促进血管SMC脱分化为合成SMC 目的：探讨CDK19 KO对血管SMC的影响 小鼠去分化为具有高增殖表型的合成SMC。我们预计这些 实验将阐明CDK19依赖的血管SMC去分化的病理生理意义 并为随后提交的R01申请创建关键的动物模型，以解决 靶向CDK19在体内抑制血管内皮生长因子的治疗作用

Vein bypass graft surgery remains the gold standard revasularization treatment for occlusive arterial diseases; however, up to 50% of the vein grafts (VGs) will occlude or fail by 10 years after surgery. VG failure (VGF) that occurs after 30 days post-surgery are mainly caused by VG intimal hyperplasia or neontima formation in which the major cell type is a highly migratory, proliferative, and secretory type of vascular smooth muscle cells (SMCs), i.e., synthetic SMCs. Recently, our lineage tracing study demonstrated that VG neointimal SMCs are mainly derived from pre-existing vascular SMCs via a process known as vascular SMC dedifferentiation or phenotypic modulation/transition. However, the molecular mechanism of vascular SMC dedifferentiation is still far from a comprehensive understanding. Thus, therapeutic targeting vascular SMC dedifferentiation to treat VGF is not yet established. In this regard, we found that cyclin-dependent kinase 19 (CDK19), an IDG-eligible protein open for study under RFA-RM-22-024, is likely a mediator of vascular SMC dedifferentiation into synthetic SMCs for VG intimal hyperplasia. Our pilot studies using CDK8/19 knockdown, CDK8/19 duo inhibitors, and CDK8 SMC- specific knockout (KO) approach in vitro and in vivo strongly support a working hypothesis that CDK19 controls the expression of a unique set of genes for vascular SMC dedifferentiation into synthetic SMCs thereby contributing to VGF. To strengthen this hypothesis, we propose 2 specific aims as follows: AIM 1 is to genetically interrogate CDK19-operated signaling network for vascular SMC dedifferentiation into synthetic SMCs with a hyper proliferating phenotype in vitro; and AIM 2 is to determine the impact of CDK19 KO on vascular SMC dedifferentiation into synthetic SMCs with a hyper proliferating phenotype in mice. We anticipate that these experiments will clarify the pathophysiological significance of CDK19-dependent vascular SMC dedifferentiation in vitro and create critical animal models for subsequent submission of an R01 application to address the therapeutic potential of targeting CDK19 in suppressing VGF in vivo.