Regulation of vascular smooth muscle cell plasticity

血管平滑肌细胞可塑性的调节

• 批准号: 8630004
• 负责人: Kathleen Ann Martin
• 金额: $ 41.63万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-03 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8630004
• 关键词: Accounting; Angioplasty; Atherosclerosis; Biology; Blood Vessels; Blood flow; Bypass; Cardiovascular Diseases; Cardiovascular system; Cell Cycle; Cell Differentiation process; Cellular biology; Chromatin; Complement; DNA; DNA Methylation; Data; Embryo; Epigenetic Process; Failure; Family; Future; Gene Expression; Genes; Goals; Growth; Growth Factor; Healed; Hematopoietic stem cells; Hyperplasia; In Vitro; Individual; Injury; Knock-out; Knockout Mice; Lead; Mediating; Mediator of activation protein; MicroRNAs; Modeling; Molecular; Molecular Conformation; Operative Surgical Procedures; Pathology; Pathway interactions; Patients; Phenotype; Platelet-Derived Growth Factor; Prevention therapy; Procedures; Process; Proteins; Regulation; Role; Sampling; Sirolimus; Smooth Muscle; Smooth Muscle Myocytes; Stem Cell Factor; Stem cells; Testing; Therapeutic; Transplantation; Vascular Diseases; Viral; c-myc Genes; cell dedifferentiation; femoral artery; graft failure; healing; improved; in vivo; in vivo Model; inhibitor/antagonist; myocardin; novel; overexpression; pluripotency; programs; promoter; public health relevance; response; restenosis; stem cell differentiation; Accounting; Angioplasty; Atherosclerosis; Biology; Blood Vessels; Blood flow; Bypass; Cardiovascular Diseases; Cardiovascular system; Cell Cycle; Cell Differentiation process; Cellular biology; Chromatin; Complement; DNA; DNA Methylation; Data; Embryo; Epigenetic Process; Failure; Family; Future; Gene Expression; Genes; Goals; Growth; Growth Factor; Healed; Hematopoietic stem cells; Hyperplasia; In Vitro; Individual; Injury; Knock-out; Knockout Mice; Lead; Mediating; Mediator of activation protein; MicroRNAs; Modeling; Molecular; Molecular Conformation; Operative Surgical Procedures; Pathology; Pathway interactions; Patients; Phenotype; Platelet-Derived Growth Factor; Prevention therapy; Procedures; Process; Proteins; Regulation; Role; Sampling; Sirolimus; Smooth Muscle; Smooth Muscle Myocytes; Stem Cell Factor; Stem cells; Testing; Therapeutic; Transplantation; Vascular Diseases; Viral; c-myc Genes; cell dedifferentiation; femoral artery; graft failure; healing; improved; in vivo; in vivo Model; inhibitor/antagonist; myocardin; novel; overexpression; pluripotency; programs; promoter; public health relevance; response; restenosis; stem cell differentiation

Project Summary/Abstract Regulation of VSMC phenotype remains a key unanswered question in vascular smooth muscle cell (VSMC) biology. VSMC retain a remarkable plasticity to de-differentiate and re-enter the cell cycle allowing for growth and healing. However, such plasticity can also contribute to severe vascular pathologies, including restenosis, graft failure, atherosclerosis, and transplant vasculopathy. Remarkably, despite intense study, the process regulating VSMC plasticity is largely unknown with few therapies successfully targeting this process. With the growing numbers of patients suffering from vascular disease the discovery of novel targets is urgently warranted. We have made the exciting discovery that de-differentiated VSMC express genes associated with stem cell pluripotency, including Sox2, Oct4, Nanog, and KLF4. We propose that these stem cell-associated genes account for the unique plasticity of mature VSMC. Recent groundbreaking studies have identified the TET (ten-eleven translocation) family of chromatin modifying proteins as key mediators of pluripotency in embryonic and hematopoietic stem cells. Our Preliminary Results implicate TET2 as an epigenetic master regulator of VSMC phenotype. Importantly, we find that TET2 inhibits expression of stem cell-associated genes and classic markers of the de-differentiated phenotype. We previously discovered that the mTORC1 inhibitor, rapamycin, promotes VSMC differentiation. We now find that rapamycin regulates TET2 expression. Remarkably, we find that TET2 also regulates miRNAs that can modulate both differentiation-specific and stem cell-associated gene expression. We hypothesize that TET2 is a master regulator of VSMC phenotype through its coordinated regulation of the promoters of contractile and stem cell-associated genes, as well as of miRNAs. In Specific Aim 1, we will determine the role of stem cell-associated genes in VSMC phenotype. In Specific Aim 2, we will determine the role of TET2-regulated miRNAs in VSMC phenotype. In Specific Aim 3, we will determine whether targeting TET2 or stem cell-associated genes has therapeutic utility in in vivo models of intimal hyperplasia. If our goals are achieved, we will have identified a novel mechanism underlying VSMC plasticity. Understanding the critical mechanisms by which mTORC1 regulates VSMC phenotype will lead to improved cardiovascular therapeutics.

项目摘要/摘要 VSMC表型的调节仍然是血管平滑中的关键未解决问题 肌肉细胞（VSMC）生物学。 VSMC保留了显着的可塑性，以脱离分化和重新输入 细胞周期允许生长和愈合。但是，这种可塑性也会有助于 严重的血管病理，包括再狭窄，移植衰竭，动脉粥样硬化和移植 血管病。值得注意的是，尽管进行了深入研究，但调节VSMC可塑性的过程是 很少有疗法成功地针对此过程，这在很大程度上未知。随着增长 患有血管疾病的患者人数迫切地发现了新靶标的发现 有必要。 我们已经提出了一个令人兴奋的发现，即脱颖而出的VSMC Express基因 与干细胞多能性有关，包括Sox2，Oct4，Nanog和KLF4。我们建议 这些与干细胞相关的基因造成了成熟VSMC的独特可塑性。 最近的开创性研究已经确定了TET（十个易位）家族 染色质修饰蛋白作为胚胎和造血的多能性介体 干细胞。我们的初步结果暗示TET2是VSMC的表观遗传学主调节器 表型。重要的是，我们发现TET2抑制了干细胞相关基因的表达 以及脱不同表型的经典标记。我们以前发现 MTORC1抑制剂雷帕霉素促进VSMC分化。我们现在发现雷帕霉素 调节TET2表达。值得注意的是，我们发现TET2还调节可以 调节分化特异性和干细胞相关基因表达。我们 假设TET2是通过其协调的VSMC表型的主调节器 收缩和干细胞相关基因以及miRNA的启动子的调节。 在特定目标1中，我们将确定与干细胞相关基因在VSMC表型中的作用。 在特定目标2中，我们将确定TET2调节的miRNA在VSMC表型中的作用。在 特定目标3，我们将确定靶向TET2或与干细胞相关的基因是否具有 内膜增生模型中的治疗效用。如果实现了目标，我们将 已经确定了一种新型的VSMC可塑性机制。了解批判 MTORC1调节VSMC表型的机制将改善 心血管疗法。