Friday, April 26, 2024
4/26/2024
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.
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