ANTISENSE TARGETED TO C-MYC MRNA INHIBITS SMOOTH MUSCLE CELL PROLIFERATION

针对 C-MYC mRNA 的反义蛋白抑制平滑肌细胞增殖

• 批准号: 3843396
• 负责人: S BIRO
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3843396
• 关键词: antisense nucleic acid; artery stenosis; biological signal transduction; cell cycle; cell growth regulation; cell migration; clone cells; coronary disorder; growth inhibitors; human tissue; intraluminal angioplasty; regulatory gene; vascular smooth muscle

Balloon dilatation of the coronary arteries is a critically important modality in treating patients suffering from coronary artery disease. Although the initial success rate is over 90%, restenosis occurs in 25 to 50% of patients weeks or months following the procedure. Restenosis is due to activation of smooth muscle cells (SMC) that normally reside in the media: after they are injured by balloon angioplasty they proliferate and migrate to the subentema, such that they can lead to restenosis. We are involved in research aimed at developing therapy to prevent restenosis. In these studies we are using antisense olygodeoxynucleotides (ODNS) to selectively inhibit growth factors that cause SMC proliferation. Proteins are synthesized by translation of mRNA. The mRNA conveys a real message; ie. it contains the code for a specific protein. This is called the "sense" message. The sequence of nucleotides that are the exact compliment of the sense mRNA is called antisense,--it does not encode a message that can be translated into a protein. The antisense sequence binds to the sense mRNA, thereby interfering with translation. Using rat aortic SMC, we have tested ODNS targeted to C-myc. C-myc is an immediate early response gene induced by various mitogens, and several lines of .'evidence derived from experiments using transformed or hematopoietic cell lines, or transgenic mice, suggest its protein product plays a role in numerous signaling transduction pathways, including those modulating cell division. We therefore reasoned that a strategy employing oligodeoxynucleotides (ODNs) complementary to c-myc mRNA (antisense ODNs) might be potent inhibitors of SMC proliferation, and perhaps of SMC migration. We found that antisense ODNs inhibited, in a concentration-dependent manner, both SMC proliferation and SMC migration. These results indicate that the c-myc gene product is involved in the signal transduction pathways mediating SMC proliferation and migration. The results also suggest a potential role of antisense strategies designed to inhibit c-myc expression for the prevention of coronary restenosis.

冠状动脉气囊扩张术是一项至关重要的 治疗冠心病患者的方式。 虽然初步成功率超过90%，但再狭窄发生在25%至 50%的患者在手术后几周或几个月内。再狭窄是 由于激活了正常情况下驻留在 媒体：在球囊血管成形术中受伤后，它们会增殖 并迁移到膜下，从而可能导致再狭窄。我们 参与了旨在开发预防疾病的治疗方法的研究 血管再狭窄。在这些研究中，我们使用了反义 氧化脱氧核苷酸(ODN)选择性抑制生长因子 导致SMC增殖。蛋白质的合成是通过翻译 MRNA.该信使核糖核酸传达了一个真实的信息；它包含一个 特定的蛋白质。这就是所谓的“感觉”信息。按顺序排列 与正义mrna完全互补的核苷酸称为 反义的--它不对消息进行编码，该消息可以翻译成 蛋白。反义序列与正义mRNA结合，从而 干扰翻译。 利用大鼠主动脉SMC，我们测试了针对C-myc的ODN。C-myc是一种 多种有丝分裂原诱导的即刻早期反应基因 从实验中获得的证据，这些证据来自于使用转化或 造血细胞系，或转基因小鼠，暗示它的蛋白质产品 在许多信号转导通路中发挥作用，包括 调节细胞分裂。因此，我们推断，一种战略 利用与c-myc mRNA互补的寡脱氧核苷酸 (反义ODN)可能是SMC增殖的有效抑制因子，并且 也许是SMC迁移的结果。我们发现反义寡核苷酸在一种 SMC增殖和迁移均呈浓度依赖性。 这些结果表明c-myc基因产物参与了 介导SMC增殖和迁移的信号转导通路。 研究结果也表明了反义策略的潜在作用。 旨在抑制c-myc的表达，以预防冠状动脉 血管再狭窄。