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