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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。