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

静脉旁路移植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（VG）将在手术后10年闭塞或失效。VG故障（VGF）， 术后30天后发生的主要是VG内膜增生或血管内膜形成， 主要的细胞类型是高度迁移、增殖和分泌型的血管平滑肌细胞（SMC）， 也就是说，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去分化或表型分化的过程从预先存在的血管SMC衍生 调制/过渡。然而，血管平滑肌细胞去分化的分子机制还远未阐明， 全面理解。因此，靶向血管SMC去分化以治疗VGF的治疗方法并不适用于血管平滑肌细胞。 尚未建立。在这方面，我们发现，细胞周期蛋白依赖性激酶19（CDK 19），一个IDG合格的蛋白开放， 对于RFA-RM-22-024下的研究，可能是血管SMC去分化为合成SMC的介导剂， VG内膜增生。我们使用CDK 8/19敲低、CDK 8/19双抑制剂和CDK 8 SMC的初步研究- 体外和体内特异性敲除（KO）方法强烈支持CDK 19控制 表达一组独特的基因，使血管SMC去分化为合成SMC， 为VGF做贡献为了加强这一假设，我们提出了两个具体的目标如下：目的1是从遗传学上 利用CDK 19调控信号网络对血管SMC去分化为合成SMC进行询问， 目的2是确定CDK 19 KO对血管SMC的影响 在小鼠中，细胞脱分化为具有过度增殖表型的合成SMC。我们预计， 实验将阐明CDK 19依赖性血管SMC去分化的病理生理学意义 并创建关键动物模型，以便随后提交R 01申请， 靶向CDK 19在体内抑制VGF中的治疗潜力。

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.