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.

静脉旁路移植手术仍然是闭塞动脉疾病的金标准重新疗法治疗。但是，多达50％的静脉移植物（VG）将在手术后10年阻塞或失败。 VG失败（VGF）手术后30天后发生，主要是由VG内膜增生或新尼氏症形成引起的主要细胞类型是一种高度迁移，增生性和分泌类型的血管平滑肌细胞（SMC），即合成SMC。最近，我们的谱系跟踪研究表明，VG新内膜SMC主要是通过称为血管SMC去分化或表型的过程源自先前存在的血管SMC 调制/过渡。但是，血管SMC去分化的分子机制仍然远离全面的理解。因此，针对血管SMC去分化VGF的治疗性靶向不是尚未建立。在这方面，我们发现依赖细胞周期蛋白的激酶19（CDK19），一种符合IDG资格的蛋白对于RFA-RM-22-024的研究 VG内膜增生。我们使用CDK8/19敲低，CDK8/19二人抑制剂和CDK8 SMC-的试点研究特定的敲除（KO）在体外和体内强烈支持CDK19控制的工作假设一组独特的基因用于血管SMC去分化为合成SMC的基因的表达为VGF做出贡献。为了加强这一假设，我们提出了2个特定目的，如下所示：目标1是基因上询问CDK19操作的信号网络，用于血管SMC推导到合成SMC中体外过度增殖表型；目标2是确定CDK19 KO对血管SMC的影响在小鼠中具有超增殖表型的合成SMC分化。我们预计这些实验将阐明CDK19依赖性血管SMC去分化的病理生理意义体外并创建关键的动物模型，以随后提交R01应用程序来解决靶向CDK19抑制VGF体内的治疗潜力。