NDRG1在血管损伤后新生内膜形成中的作用及其分子机制

Restenosis following percutanous coronary intervention(PCI) limits the long-term outcome of percutanous coronary intervention. There have no efficient clinical drug for preventing restenosis after PCI up to now. The major pathological change of restenosis is neointima formation, which the cell origination and molecular mechanism are still large unkown. PDGF and TGFβplay the key roles in neointima formation after vascular injury. NDRG1, a well-known tumor suppress gene, has important roles in cell differentiation and proliferation and migration. Recently, we found that both PDGF and TGFβcould regulate the expression of NDRG1. Primary data from rat carotid artery balloon injury model by us indicated that NDRG1 maybe involved in the neointima formation. So, we proposed a hypothesis that the expression of NDRG1 would be induced following TGFβincreasing during the early stage of vascular injury and suppressed by PDGF stimulation during the late stage of vascular injury, which change of NDRG1 expression would be contributed to neointima formation. In this study, rat carotid artery balloon injury model will be used as in vivo model to study the functions of NDRG1 in neointima formation, and mesenchyma stem cells (C3H10T1/2 cells) and primary cultured vascular smooth mscle cells(VSMCs) will be repectively used as in vitro models to study the function and molecular mechanism in vascular smooth muscle differentiation and proliferation and migration. The aims of this study are to elucidate the roles and molecular mechanism of NDRG1 in neointima formation and provide a new potential target for clinical preventing restenosis.

再狭窄是动脉介入手术后最为常见的并发症，严重影响其疗效。目前为此，还没有合适的药物或方法解决这一问题。新生内膜形成是再狭窄的主要病理变化，但其形成中细胞的来源及分子机制仍未完全阐明。PDGF和TGFβ是新生内膜形成过程中两个重要的细胞因子。NDRG1，已知的肿瘤抑制因子，具有抑制增殖，促进分化等多种生物学作用。我们最近发现NDRG1能同时受PDGF和TGFβ的调控，初步实验结果也提示NDRG1参与新生内膜的形成。据此，我们猜测在血管损伤早期，TGFβ诱导NDRG1表达，而在晚期PDGF则抑制其表达，从而调节其对新生内膜的抑制作用。本项目我们拟用球囊拉伤模型研究NDRG1对新生内膜的作用，并进一步用C3H10T1/2和原代培养血管平滑肌细胞来研究NDRG1对平滑肌细胞的分化和增殖迁移的作用及其分子机制。通过这些研究明确NDRG1在新生内膜形成中的作用，为临床上治疗再狭窄提供新的潜在靶点。

再狭窄是动脉介入手术后最为常见的并发症，严重影响其疗效。到目前为止，还没有合适的药物或方法能解决这一问题。新生内膜形成是再狭窄的主要病理变化，但其形成的分子机制仍未阐明。在本项目中，我们证实NDRG1在血管损伤后新生内膜形成过程中发挥重要作用，机制上，NDRG1通过抑制CDK1 Thr161位点磷酸化和激活CDK1 Thr14/Tyr15位点磷酸化从而抑制PCNA的表达，抑制细胞的增殖和迁移。进一步证实细胞因子PDGF-BB能够通过PI3K通路抑制NDRG1的表达，表明NDRG1参与PDGF-BB介导的平滑肌细胞的表型转换和增殖迁移过程。这些结果表明NDRG1可能作为临床上治疗再狭窄的一个潜在分子靶标。除此之外，我们还发现Nupr1在TGFβ诱导的血管平滑肌细胞的分化过程中起重要作用。另外我们还对甲基苯丙胺（METH）导致的心血管系统和神经系统的毒性作用及其机制进行了研究，鉴定了一系列的分子，如C/EBPβ, PUMA, DDIT4, Caspase-11, Nupr1等分子在METH诱导的神经细胞、心肌细胞及血管内皮细胞的凋亡和自噬中发挥重要作用。在Mol Neurobiol., Front Mol Neurosci., Cell Death Dis., Toxicol Appl Pharmcol., Toxicol Sci., Toxicol Lett., BBA-Mol Basis Dis 等杂志上发表SCI论文8篇。