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

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.

项目概要/摘要 VSMC表型的调节仍然是血管平滑肌中尚未解决的关键问题 肌细胞（VSMC）生物学。 VSMC 保留显着的可塑性以去分化和重新进入 细胞周期允许生长和愈合。然而，这种可塑性也有助于 严重的血管病变，包括再狭窄、移植失败、动脉粥样硬化和移植 血管病变。值得注意的是，尽管进行了大量研究，调节 VSMC 可塑性的过程仍然是 很大程度上未知，很少有疗法成功针对这一过程。随着日益增长的 大量患有血管疾病的患者迫切需要发现新的靶点 保证。 我们取得了令人兴奋的发现：去分化的VSMC表达基因 与干细胞多能性相关的基因，包括 Sox2、Oct4、Nanog 和 KLF4。我们建议 这些干细胞相关基因解释了成熟 VSMC 的独特可塑性。 最近的突破性研究已经确定了 TET（10-11 易位）家族 染色质修饰蛋白作为胚胎和造血细胞多能性的关键介质 干细胞。我们的初步结果表明 TET2 是 VSMC 的表观遗传主调节因子 表型。重要的是，我们发现 TET2 抑制干细胞相关基因的表达 和去分化表型的经典标记。我们之前发现， mTORC1 抑制剂雷帕霉素可促进 VSMC 分化。现在我们发现雷帕霉素 调节 TET2 表达。值得注意的是，我们发现 TET2 还调节 miRNA 调节分化特异性和干细胞相关基因表达。我们 假设 TET2 通过其协调性是 VSMC 表型的主要调节者 收缩和干细胞相关基因以及 miRNA 启动子的调控。 在具体目标 1 中，我们将确定干细胞相关基因在 VSMC 表型中的作用。 在具体目标 2 中，我们将确定 TET2 调节的 miRNA 在 VSMC 表型中的作用。在 具体目标3，我们将确定针对TET2或干细胞相关基因是否具有 在内膜增生的体内模型中的治疗用途。如果我们的目标实现了，我们将 已经确定了 VSMC 可塑性的一个新机制。了解关键 mTORC1 调节 VSMC 表型的机制将导致改善 心血管治疗。