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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：
10829610
负责人：
Taixing Cui
金额：
$ 48.62万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
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/10829610
关键词：
Amino Acids Aorta Binding Bioinformatics Blood Vessels Bypass Carotid Arteries Cell Separation 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 Metabolic Metabolic Control Metabolism Molecular Mus Muscle Cells Operative Surgical Procedures Outcome Pathogenesis Pathway interactions Phenotype Pilot Projects Process Proliferating 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，这是许多平滑肌细胞的标志。闭塞性血管疾病，与代谢开关，其特征是增加有氧糖酵解也促进甲羟戊酸代谢，降低葡萄糖氧化，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（CDK 8）是一个主要的调节因子，血管平滑肌细胞去分化的代谢控制内膜增生血管闭塞。机制研究发现，CDK 8控制SREBP 2（固醇调节元件结合因子-2）操纵的转录，以促进蛋白质香叶基香叶基化的甲羟戊酸代谢，驱动血管SMC去分化。因此，我们提出了一种新的范式，其中CDK 8控制着细胞周期。甲羟戊酸代谢的蛋白质香叶基香叶基化，促进血管平滑肌细胞的去分化，内膜增生，从而导致闭塞性血管疾病。我们将测试这个假设，描述CDK 8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CDK 8在血管SMC去分化为合成的SMC中的介导作用。平滑肌细胞内膜增生向血管闭塞;目标2将确定潜在的分子机制，重点是CDK 8操作甲羟戊酸代谢的分子网络蛋白质香叶基香叶基化的途径，这是血管SMC去分化为合成 SMC导致内膜增生，进而导致血管闭塞。这份提案将提供第一次评估， CDK 8介导的闭塞性血管病变的形成，并定义了一种新的闭塞性血管病变的途径。由先前未被识别的CDK 8操作的代谢重编程介导的血管重构从而为血管平滑肌细胞可塑性的研究以及血管平滑肌细胞的发育提供了新的思路。闭塞性血管疾病的创新和有效的治疗方法。