Metabolic control of vascular smooth muscle cell plasticity

血管平滑肌细胞可塑性的代谢控制

基本信息

批准号：
10334766
负责人：
Taixing Cui
金额：
$ 63.62万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10334766
关键词：
Amino Acids Binding Bioinformatics Blood Vessels Bypass Carotid Arteries ChIP-seq Cues Cyclin-Dependent Kinases DNA Data Development Disease Exhibits Failure Genetic Transcription Glass Glucose Hyperplasia In Vitro Investigation Knockout Mice Lesion Ligation Light Link LoxP-flanked allele Maps Mediating Mediator of activation protein Metabolic Metabolic Control Metabolism Molecular Mus Muscle Cells Operative Surgical Procedures Outcome Pathogenesis Pathway interactions Phenotype Pilot Projects Process Protein Geranylgeranylation Proto-Oncogene Proteins c-akt Regulatory Element Role Scheme Signal Pathway Signal Transduction Smooth Muscle Myocytes Sterols Testing Vascular Diseases Vascular Smooth Muscle Vascular remodeling Vein graft aerobic glycolysis beta Actin cell dedifferentiation clinically relevant combat effective therapy fatty acid oxidation in vivo inhibitor innovation insight mevalonate mouse model novel overexpression oxidation protein metabolism small molecule inhibitor targeted treatment therapeutically effective transcriptome sequencing

项目摘要

The dedifferentiation of vascular smooth muscle cells (SMCs) into synthetic SMCs, a hallmark of many occlusive vascular diseases, is associated with a metabolic switch that is characterized by increased aerobic glycolysis, which also fuels mevalonate metabolism, decreased glucose oxidation and increased fatty acid oxidation. However, the molecular links between environmental cues and the metabolic reprogramming remain poorly understood. Our pilot studies revealed that cyclin dependent kinase 8 (CDK8) is a master regulator of the metabolic control of vascular SMC dedifferentiation for intimal hyperplasia toward vascular occlusion. Mechanistic investigations uncovered that CDK8 controls the SREBP2 (sterol regulatory element binding factor-2)-operated transcription to promote the mevalonate metabolism for protein geranylgeranylation, which drives the vascular SMC dedifferentiation. Thus, we propose a novel paradigm in which CDK8 controls the mevalonate metabolism for protein geranylgeranylation to promote the dedifferentiation of vascular SMCs for intimal hyperplasia, thereby contributing to occlusive vascular disease. We will test this hypothesis and delineate the molecular mechanisms of CDK8-operated metabolic control of vascular SMC dedifferentiation by 2 specific aims: Aim 1 will establish a mediator role of CDK8 in vascular SMC dedifferentiation into synthetic SMCs for intimal hyperplasia toward vascular occlusion; Aim 2 will determine the underlying molecular mechanisms with a focus on the molecular network by which CDK8 operates the mevalonate metabolism pathway for protein geranylgeranylation which is required for vascular SMC dedifferentiation into synthetic SMCs leading to intimal hyperplasia toward vascular occlusion. This proposal will provide the first assessment of CDK8-mediated occlusive vascular lesion formation and define a novel pathway of occlusive vascular remodeling that is mediated by previously unrecognized CDK8-operated metabolic reprogramming for vascular SMC dedifferentiation, thus shedding light on the study of vascular SMC plasticity as well as the development of innovative and effective therapeutic approaches for occlusive vascular disease.

血管平滑肌细胞 (SMC) 去分化为合成 SMC，这是许多细胞的标志闭塞性血管疾病，与代谢转换相关，其特征是有氧运动增加糖酵解，也促进甲羟戊酸代谢，减少葡萄糖氧化并增加脂肪酸氧化。然而，环境因素和代谢重编程之间的分子联系仍然存在不太了解。我们的初步研究表明，细胞周期蛋白依赖性激酶 8 (CDK8) 是血管 SMC 去分化的代谢控制，内膜增生导致血管闭塞。机制研究发现 CDK8 控制 SREBP2（甾醇调节元件结合因子 2) 操作的转录促进蛋白质香叶基香叶基化的甲羟戊酸代谢，其中驱动血管 SMC 去分化。因此，我们提出了一种新的范例，其中 CDK8 控制甲羟戊酸代谢促进蛋白质香叶基香叶基化促进血管平滑肌细胞去分化内膜增生，从而导致闭塞性血管疾病。我们将检验这个假设并描述 CDK8 操作的血管 SMC 去分化代谢控制的分子机制 2 个具体目标：目标 1 将建立 CDK8 在血管 SMC 去分化为合成细胞中的介导作用平滑肌细胞促进内膜增生，导致血管闭塞；目标 2 将确定潜在的分子重点关注 CDK8 操纵甲羟戊酸代谢的分子网络的机制蛋白质香叶基香叶基化途径，这是血管 SMC 去分化为合成所需的平滑肌细胞导致内膜增生导致血管闭塞。该提案将提供第一次评估 CDK8介导的闭塞性血管病变形成的机制，并定义了闭塞性血管病变的新途径由先前未被识别的 CDK8 操作的血管代谢重编程介导的重塑 SMC去分化，为血管SMC可塑性研究及发展提供线索闭塞性血管疾病的创新和有效的治疗方法。