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

细胞周期蛋白依赖性激酶（CDK）19介导的静脉移植内膜增生

基本信息

批准号：
10664327
负责人：
Taixing Cui
金额：
$ 15.65万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10664327
关键词：
Address Adult Angioplasty Animal Model Applications Grants Area Arterial Occlusive Diseases Atherosclerosis Blood Vessels Bypass Cardiovascular Diseases Carotid Arteries Cells Complex Cues Cyclin-Dependent Kinases Development Disease Drug Targeting Eligibility Determination Failure Genes Genetic Transcription Growth Hyperplasia In Vitro Individual Knock-out Knockout Mice Legal patent Lesion Ligation Link LoxP-flanked allele Macrophage Mediating Mediator Minor Modeling Molecular Mus Nature Operative Surgical Procedures Outcome Phenotype Pilot Projects Process Proliferating Proteins Regulation Research Role Signal Transduction Small Interfering RNA Smooth Muscle Myocytes Stenosis Testing Therapeutic Thick Vascular Diseases Vascular Smooth Muscle Vein graft Veins cell dedifferentiation cell type conditional knockout cyclin C experimental study graft failure in vivo inhibitor innovation knock out mouse project knock-down mouse model novel preference programs repaired restenosis stem cells stem-like cell success therapeutic target transcriptome sequencing vascular contributions vascular smooth muscle cell proliferation

项目摘要

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.

静脉搭桥手术仍然是闭塞性动脉疾病血运重建治疗的金标准；然而，高达 50% 的静脉移植物 (VG) 会在术后 10 年内闭塞或失败。 VG 故障 (VGF) 术后30天后发生的主要是VG内膜增生或新生瘤形成引起的，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（SMC），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 去分化或表型的过程衍生自预先存在的血管 SMC 调制/转换。然而，血管SMC去分化的分子机制仍远未完全阐明。全面的了解。因此，靶向血管 SMC 去分化来治疗 VGF 并不适用。尚未成立。在这方面，我们发现细胞周期蛋白依赖性激酶 19 (CDK19)，一种 IDG 合格的蛋白质，开放 RFA-RM-22-024 下的研究，可能是血管 SMC 去分化为合成 SMC 的介质 VG内膜增生。我们的初步研究使用 CDK8/19 敲低、CDK8/19 双抑制剂和 CDK8 SMC- 体外和体内特异性敲除 (KO) 方法强烈支持 CDK19 控制的工作假设一组独特基因的表达，使血管 SMC 去分化为合成 SMC 为 VGF 做出贡献。为了强化这一假设，我们提出了 2 个具体目标如下：目标 1 是从遗传角度询问 CDK19 操作的信号网络，以将血管 SMC 去分化为合成 SMC 体外过度增殖表型；目的2是确定CDK19 KO对血管SMC的影响在小鼠体内去分化为具有过度增殖表型的合成 SMC。我们预计这些实验将阐明CDK19依赖性血管SMC去分化的病理生理学意义体外并创建关键动物模型，以便随后提交 R01 申请来解决靶向CDK19在体内抑制VGF的治疗潜力。